The Asia–Pacific Working Party on Non-Alcoholic Fatty Liver Disease

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doi:10.1111/jgh.13856

REVIEW The Asia–Paciﬁc Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017—Part 2: Management and special groups Shiv Chitturi,* Vincent Wai-Sun Wong,†,‡ Wah-Kheong Chan,§ Grace Lai-Hung Wong,†,‡ SimonKin-HungWong,¶ Jose Sollano,** Yen-Hsuan Ni,†† Chun-Jen Liu,‡‡ Yu-Cheng Lin,†† Laurentius Adrianto Lesmana,§§ Seung Up Kim,¶¶ Etsuko Hashimoto,*** Masahide Hamaguchi,††† Khean-Lee Goh,§ Jiangao Fan,‡‡‡ Ajay Duseja,§§§ Yock Young Dan,¶¶¶ Yogesh Chawla,§§§ Geoff Farrell* and Henry Lik-Yuen Chan†,‡

*Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia; †Department of Medicine and Therapeutics, ‡State Key Laboratory of Digestive Disease, ¶Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong; §Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia; **University of Santo Tomas, Manila, Philippines; ††Hepatitis Research Center, National Taiwan University, and ‡‡Department of Internal Medicine, Hepatitis Research Center, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan; §§Digestive Disease and GI Oncology Centre, Medistra Hospital, Jakarta, Indonesia; ¶¶Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea; ***Department of Internal Medicine and Gastroenterology, Tokyo Women’s Medical University, Tokyo and †††Department of Diabetology, Kameoka Municipal Hospital, Kameoka, Japan; ‡‡‡Xin Hua Hospital Afﬁliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; §§§Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India; and ¶¶¶Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Key words Management metabolic syndrome, NAFLD, NASH, nonalcoholic steatohepatitis, obesity, obeticholic acid, pioglitazone, vitamin E. How to assess efficacy of interventions. In clinical practice, and particularly among those who appear to have mild liver disease, it may be sufficient to note changes Accepted for publication 25 June 2017. (normalization) of liver tests and serum lipids/blood glucose in relation to lifestyle intervention and weight reduction. However, this is not sufficient for clinical trials because (i) Correspondence liver pathology is not defined unless biopsy is performed and (ii) the only legitimate surro- Professor Geoff C Farrell, Gastroenterology and Hepatology Unit, The Canberra Hospital, PO Box gate marker for an improved clinical outcome of liver disease is improvement in liver fi 11, Woden, Canberra, ACT 2606, Australia. brosis. Email: [email protected] Towards the latter goal, reversal of non-alcoholic steatohepatitis (NASH) pathology at fi Dr Vincent Wai-Sun Wong, Department of Med- present seems most useful as the change most likely to prevent brosis progression or re- icine and Therapeutics, The Chinese University versal, noting that reversal of liver fibrosis with resolution of NASH has now been clearly of Hong Kong, 9/F, Clinical Sciences Building, documented in weight reduction studies. The most robust endpoint for studies of NASH Prince of Wales Hospital, 30-32 Ngan Shing with liver fibrosis but not cirrhosis would be the reversal of NASH and improvement of fi- Street, Shatin, Hong Kong. brosis either by fibrosis score on semi-quantitative measurements of collagen density. This Email: [email protected] recommendation accords with recent recommendations of a US Food and Drug Adminis- tration (FDA) and American Association for the Study of Liver Diseases Joint Working Declaration of conflict of interest: Vincent Wong Party and is already being introduced post hoc into major ongoing studies of new drug served as a consultant for AbbVie, Allergan, Gilead treatments for NASH. Sciences, Janssen, Perspectum Diagnostics, and At present, an endpoint for trials of NASH with cirrhosis is more difficult to define as Pfizer and a speaker for Bristol-Myers Squibb, cirrhosis reversal may not occur, and longer-term clinical outcomes or surrogate measures Echosens, Gilead Sciences, and Merck. Yock of these (e.g. reduction in wedged hepatic vein pressure) are ideally required. Young Dan served as an advisory board member The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) is relatively unin- and has received research grants from AbbVie, formative in several large studies. Several studies have also shown that it is inappropriate Bristol-Myers Squibb, and Gilead Sciences. Khean- to diagnose NASH based on NAS because significant weighting (3 out of 8 points) is Lee Goh served as an advisory board member of given to the degree of hepatic steatosis.1 Improvement or reversal of steatosis has not Gilead Sciences and a speaker for AbbVie and Gil- been shown to correlate well with reversal of NASH or liver fibrosis. Improvement in ead Sciences. Grace Wong has served as an advi- NAS also does not weigh the fibrosis component, and the addition of “failure to worsen sory committee member for Otsuka and Gilead. fi ” She has also served as a speaker for Abbott, brosis score may be not be a satisfactory cut-off for a disease-intervening treatment. Abbvie, Bristol-Myers Squibb, Echosens, Furui, Besides, NAS does not correlate well with long-term clinical outcomes, particularly after fi 2 “ fi Gilead, Janssen, Otsuka, and Roche. Henry Chan adjustment for brosis stage. Therefore, resolution of NASH without worsening in - served as an advisor for AbbVie, Bristol-Myers brosis” and “fibrosis improvement without worsening of NASH” are now used in phase Squibb, Gilead, Janssen, and Roche and a speaker 3 studies as primary endpoints. for AbbVie, Bristol-Myers Squibb, Echosens, The utility of surrogate (non-invasive) markers as primary endpoints of phase 1 or Gilead, Novartis, and Roche. phase 2a studies in NASH is controversial. A hope is that biomarker and physical indica- Financial support: This project was supported by a tors of inflammatory severity and fibrosis may substitute liver biopsy to facilitate conduct grant from the Journal of Gastroenterology and of such studies, but at present, the evidence allowing this is not sufficiently robust to ei- Hepatology Foundation. ther “rule in” or “rule out” pharmacological agents before proceeding to larger-scale

86 Journal of Gastroenterology and Hepatology 33 (2018) 86–98 © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd S Chitturi et al. Asia-Pacific NAFLD guidelines studies. On the other hand, the use of physical markers of liver Exercise considerations. The intensity, volume, and type of steatosis (which actually determine hepatic triglyceride content) exercise required are debated. Ischemic heart disease is the leading such as magnetic resonance spectroscopy may be flawed for a cause of death in NAFLD.14,15 For the general population, physi- liver disease (NASH) whose greatest clinical importance relates cal activity guidelines recommend 30 min/day of moderate-inten- to fibrosis and possibly liver cell injury and liver inflammation. sity exercise for ≥ 5 days/week or a total of ≥ 150 min/week or This working party does not accept magnetic resonance imaging vigorous-intensity exercise for ≥ 20 min/day on ≥ 3 days/week as a substitute for liver biopsy in NASH studies. On the other (≥ 75 min/week).16 Resistance exercise on 2–3 days/week and hand, while non-invasive tests of fibrosis such as transient flexibility exercises > 2 days/week are also recommended. Only elastography have been extensively evaluated in cross-sectional limited data on exercise intensity are available with respect to pa- studies of NAFLD patients, their role as a monitoring tool should tients with NASH. In one US study based on self-reported physical be further explored in longitudinal studies. activity, only vigorous activity (75 min/week) was associated with a reduced likelihood of having NASH (odds ratio 0.65, 95% con- fidence interval [CI] 0.45–0.98) or advanced fibrosis (odds ratio Lifestyle management 0.53, 95% CI 0.29–0.97).17 A Japanese study found a dose– response relationship between exercise volume and reduction in Diet and exercise programs. Several studies have evaluated liver fat, with greater response in subjects exercising over lifestyle changes (diet and physical activity) in managing NAFLD. 250 min/week as compared with those exercising for less than Initial studies correlated histologic improvement with a 7% reduc- 150 min/week.18 Resistance and aerobic exercise training have tion in body weight.3 Exercise can independently improve hepatic similar effects on hepatic steatosis,19 but one systematic review steatosis without weight loss,4 but weight loss is usually required concluded that the former involved lesser energy consumption for NASH resolution.5 A key Cuban lifestyle management pro- and therefore could be offered for patients unable to undertake aer- gram (n = 293) showed a clear dose–response between weight loss obic training.20 and improvement in liver histology; 58% of those achieving > 5% High-intensity interval training can also reduce hepatic fat but and 90% of those achieving weight loss of > 10%, respectively, like all other exercise regimes has not independently been shown showed resolution of NASH. Only the latter showed improvement to improve NASH.21 in fibrosis stage (in 45%).5 A systematic review published in 2012 (23 studies, including seven randomized and six controlled trials) had already noted the importance of lifestyle intervention strategies.6 The included trials Special considerations in patients with non-alcoholic fatty differed in design, with some involving diet (n = 11) or exercise liver disease. Patients with NAFLD are often sedentary with alone (n = 2), but the majority (n = 19) combined both modalities. low levels of cardiorespiratory fitness22 and motivation. One US There was a trend towards reduced inflammatory activity in five study found that nearly a third of their patients were uninterested studies, with two showing statistical significance. Data on fibrosis in making weight-related behavioral changes23 and only 20% reduction were seen only in one study.6 Combined diet/exercise achieved a weight loss of 5% over an 18-month period.24 There- strategies are more effective in reducing liver fat than either mo- fore, multidisciplinary management with a dietician, psychologist, dality alone (49.8% vs 30.2%, respectively).7 Asian data support and exercise trainer is needed to achieve desired goals.25 a 10% weight reduction target, although some individuals (up to 40%) can improve with lesser degrees (3% to 5%) of weight 8,9 loss. There are no Asian data supporting NASH resolution Pharmacological treatment. Although lifestyle manage- through lifestyle changes, and this is a priority for future research. ment is effective and should be encouraged, not all patients can ad- here to diet and exercise. Besides, it is difficult for patients with Dietary considerations. Individuals with NAFLD tend to con- morbid obesity and musculoskeletal disorders to do sufficient ex- sume energy-dense foods, rich in saturated fat, cholesterol, and ercise. Therefore, pharmacological treatment may be required in sugar-sweetened beverages but deficient in micronutrients found some patients. As illustrated in previous sections, patients with in fresh fruit, fiber and green vegetables, and omega-3 polyunsat- simple steatosis run a benign course and have a low risk of liver- urated fatty acids (n-3 PUFA).10 Therefore, dietary plans should related complications. We should therefore target patients with address these imbalances that are important in preventing/ NASH and/or liver fibrosis.26 At present, no drug has been ap- managing coexisting metabolic and cardiovascular disease proved by the US FDA or the European Medicines Agency for (CVD). However, n-3 PUFA supplementation has not shown to the treatment of NASH. However, some agents have entered phase be beneficial in improving NASH.11 The aim should be for gradual 3 development. Besides, a number of agents with indications for weight loss (up to 1 kg/week) with a hypocaloric diet (500– other medical conditions have also been tested in NASH patients. 1000 kcal deficit) because crash diets can worsen NASH. Several Nonetheless, it is important to note that Asian patients are under- different diet protocols have been proposed (low carbohydrate, represented in NASH trials, and the data discussed in this section low fat, and Mediterranean diet).12 While there are short-term dif- are mostly from international trials with the majority of patients ferences with respect to weight loss and reduction in steatosis, being Caucasians. In addition, the available clinical trials typically these differences are no longer significant with longer follow apply extensive exclusion criteria and have limited generalizabil- up.13 Very-low-calorie diets are unsustainable and are used mainly ity. For instance, the safety and efficacy of the drugs in cirrhotic in preparation for bariatric surgery. Finally, there are no data to patients are largely unknown. Table 1 summarizes the agents support any specific diet with respect to the resolution of NASH. discussed in this section.

Journal of Gastroenterology and Hepatology 33 (2018) 86–98 87 © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd Asia-Pacific NAFLD guidelines S Chitturi et al.

Table 1 Existing pharmacological agents and agents entering phase 3 development with potential effect on NASH

Drug/drug class Mode of action Improve NASH Improve liver ﬁbrosis Notes

Vitamin E Anti-oxidant Yes No Thiazolidinediones Insulin sensitizer Yes Inconsistent results Elafibranor Peroxisome proliferator-activated Yes Only in patients with receptor-α and δ agonist improvement in NASH Pentoxifylline Anti-inflammatory; weak antitumor Possible? One small RCT only necrosis factor-α action Metformin Insulin sensitizer No No No effect—several meta-analyses Glucagon-like peptide-1 Reduce appetite and increase insulin Yes May prevent fibrosis Given as injections and may cause receptor agonists sensitivity progression gastrointestinal upset Dipeptidyl peptidase-4 Increase incretin levels Unknown Unknown inhibitors Obeticholic acid Stimulates farnesoid X receptor Yes Yes Omega-3 fatty acids Anti-inflammatory and potential effects on lipid metabolism

NASH, non-alcoholic steatohepatitis; RCT, randomized controlled trial.

Vitamin E. Oxidative stress is considered to be a key mechanism overall NASH resolution rate was 51%.36 Resolution of NASH of hepatocellular injury and disease progression in NASH patients. tends to be mainly in the first year,37 but continued use is neces- Vitamin E is an anti-oxidant and has been investigated to treat sary to maintain histologic improvement.38 Adverse effects in- NASH. In the PIVENS trial, vitamin E at a dose of 800 IU/day clude weight gain (mean, 4.4 kg) and other safety concerns of α-tocopherol for 96 weeks is associated with a decrease in se- including myocardial infarction (rosiglitazone) and increased frac- rum aminotransferases and histologic improvement in steatosis, in- ture risk, congestive cardiac failure, and bladder cancer (pioglita- flammation, and ballooning and resolution of steatohepatitis in zone).39–41 adults with NASH.27 In a randomized, vitamin E-controlled trial Dual PPAR-α, δ agonist elafibranor (a) was evaluated in a phase of bicyclol plus metformin in Chinese patients with NAFLD and IIb randomized controlled trial (RCT).42 Patients with NASH impaired fasting glucose, vitamin E at a dose of 300 mg/day for (n = 276) received 80 or 120 mg of elafibranor or placebo for 24 weeks is not better than bicyclol in the improvement of serum 52 weeks. The primary endpoint of NASH resolution without aminotransferase and in hepatic histological changes.28 However, worsening of fibrosis was not achieved (21%, 23%, and 17%, re- vitamin E has no effect on hepatic fibrosis, insulin resistance, spectively; P = NS) but a post hoc-modified endpoint (no hepato- and serum low-density lipoprotein cholesterol level.29 Individuals cyte ballooning and no/mild lobular inflammation without fibrosis with resolution of NASH may still be at increased risk of type 2 progression) was observed in 19%, 13%, and 12%, respectively diabetes (T2DM) and CVD. In addition, concerns about long-term (P = 0.045). There were favorable effects on the lipid profile, lack safety of vitamin E exist, mainly an increase in all-cause mortal- of weight gain, but a mild reversible creatinine increase was seen ity,30 in hemorrhagic stroke,31 and prostate cancer in relatively in 4%. healthy males older than 50 years.32 Asian data on the use of PPAR agonists are scarce. In one Indian study, pioglitazone appears to have better metabolic and histological benefits than pentoxifylline.43 Thiazolidinediones and other peroxisome proliferator-activated receptor agonists. Ligands (α, δ, and Pentoxifylline. Pentoxifylline is a phosphodiesterase inhibitor γ) of peroxisome proliferator-activated receptors (PPARs) improve with anti-oxidant properties and was originally proposed to inhibit insulin sensitivity and hepatic fatty acid oxidation and have antitumor necrosis factor-α (TNF-α) production. Improvement in inflammatory effects. steatohepatitis was documented in methionine–choline deficient Trials with fibrates (clofibrates), which are PPAR-α agonists and high-fat diet-induced models of NASH, even in the absence (clofibrate), have been disappointing,33 but they remain useful in of any change in serum or hepatic TNF.44 Pilot, non-randomized managing hypertriglyceridemia. studies in human NASH also showed improvement in serum ami- A 2011 meta-analysis of seven randomized trials involving notransferases and histology, but again without impact on serum PPAR-γ agonists (thiazolidinediones) showed significant reduction TNF.45 A subsequent RCT showed no significant histologic differ- in hepatic steatosis (relative risk [RR] 2.0, CI 1.57–2.6), lobular ences between the treatment and control groups.46 In another RCT, inflammation (RR 1.7, CI 1.3–2.2), and hepatocellular ballooning pentoxifylline failed to reduce hepatocyte ballooning yet achieved (RR 1.6, CI 1.15–2.3), with no or modest effects on fibrosis (RR statistically but not clinically significant reduction in fibrosis (À0.2 1.38, CI 1.01–1.89).34 Some trials have excluded high-risk pa- vs +0.4 fibrosis stage among those on pentoxifylline vs placebo).47 tients (T2DM or cirrhosis), and pioglitazone appears to work as There are also safety concerns about pentoxifylline as some well in nondiabetic patients.35 A recent trial tried to address this adverse events were noted in previous trials in alcoholic limitation by including patients with prediabetes or T2DM but still hepatitis (e.g. gastrointestinal upset and infection). Therefore, included only 10% to 14% with advanced liver fibrosis. The pentoxifylline cannot be recommended.

88 Journal of Gastroenterology and Hepatology 33 (2018) 86–98 © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd S Chitturi et al. Asia-Pacific NAFLD guidelines

Metformin. Because insulin resistance plays a central role in the also been shown to reduce cardiovascular deaths, myocardial in- pathogenesis of NAFLD, insulin-sensitizing drugs including met- farction, and stroke in diabetic patients (hazard ratio 0.87).64 All formin have been used in the treatment of patients with NAFLD. GLP-1 agonists are given as injections. Although there has been After its usefulness in reversing fatty liver was shown in leptin- no study on Asian NASH patients, the pharmacokinetics of deficient ob/ob mice, metformin was first used in humans in a pilot GLP-1 agonists do not appear to differ between Asian and study of 20 patients with NASH, and in comparison with six non-Asian patients.65,66 GLP-1 agonists also appear to reduce controls was shown to improve hepatic transaminases, insulin glycated hemoglobin more effectively in Asian patients with sensitivity, and liver volume.48,49 Thereafter, several other studies, T2DM.67 including one from Asia, have shown its utility in improving In contrast, DDP-4 inhibitors do not seem to reduce weight. serum biochemistry and insulin resistance, but the randomized There are conflicting data on their effect on hepatic steatosis based data showing histological improvement with metformin are on radiological assessment.68,69 Furthermore, histological data are sparse.50–53 One of the first randomized trials in which metformin lacking. (2 g/day) given for 12 months was compared with vitamin E or weight reducing diet showed it to be effective in improving the aminotransferase levels and histological reduction in liver fat, Obeticholic acid. Obeticholic acid is a potent agonist of the necroinflammation, and fibrosis in a small number of liver biopsies 54 farnesoid X receptor, which is responsible for not only bile acid performed only in the metformin group. Another randomized, but also glucose and lipid metabolism. It has been approved by – placebo controlled study that used metformin (2.5 3 g/day) for the US FDA for the treatment of primary biliary cholangitis. In 6 months did not show any difference in computed tomography the phase 2 FLINT study in patients with biopsy-proven NASH, or histologically assessed steatosis, NAS, liver transaminases, or 55 a histological response of reduction in the NAFLD activity score insulin resistance in comparison with controls. Similarly, in an- by 2 points or more with no worsening of fibrosis was achieved other placebo-controlled trial, even though metformin improved 56 in 45% of patients receiving obeticholic acid and 21% of those re- insulin resistance, it failed to improve the liver histology. Even ceiving placebo for 72 weeks.70 Patients receiving obeticholic acid though mild gastrointestinal disturbances have been reported, none were also more likely to have improvement in fibrosis (35% vs of the studies using metformin reported any major side effects like 54–56 19%). In another phase 2 trial in Japanese NASH patients, hypoglycemia or lactic acidosis. Metformin is safe and ap- obeticholic acid only increased the proportion of patients achiev- pears to reduce the risk of hepatocellular carcinoma (HCC) in an- 57,58 ing the same histological endpoint as in the FLINT study when imal and observational studies. On the other hand, as shown in it was given at a very high dose of 40 mg daily, which will likely several meta-analyses, metformin does not reduce liver fat or im- be limited by side effects (only top line results announced). Pruri- prove liver histology and therefore cannot be recommended as a 59–61 tus is a common side effect of obeticholic acid. The drug also primary treatment for NAFLD/NASH. causes an atherogenic lipid profile with high total cholesterol and low-density lipoprotein cholesterol, as well as reduced high- density lipoprotein cholesterol. The impact on cardiovascular out- Glucagon-like peptide-1 receptor agonists and dipeptidyl come should be clarified. The REGENERATE study peptidase-4 inhibitors. Glucagon-like peptide-1 (GLP-1) ago- (ClinicalTrials.gov Identifier NCT02548351) is an ongoing phase nists and dipeptidyl peptidase-4 (DPP-4) inhibitors are newer 3 study testing obeticholic acid in NASH patients. drugs to treat T2DM by modulating beta-cell responsiveness. The GLP-1 agonist liraglutide has also been registered for the treatment of obesity and overweight with weight-related conditions. GLP-1 is secreted by intestinal L cells in response to nutri- Omega-3 fatty acid. A systematic review concluded that n-3 ents and acts as an incretin by increasing insulin secretion and PUFAs supplementation may reduce liver fat at a dose of decreasing glucagon secretion. It suppresses appetite centrally ≥ 0.83 g/day.71 However, no significant improvement was seen and delays gastric emptying, the latter further contributing to re- on liver function tests. A recent meta-analysis supports the use duced food intake. DDP-4 catalyzes the degradation of circulating of n-3 PUFAs because it may lower liver enzyme (gamma- incretins. DPP-4 inhibitors thus exert metabolic effects by raising glutamyltransferase) and blood lipid levels (tryglycerides and serum incretin levels. high-density lipoprotein cholesterol).72 Studies addressing liver One RCT (the liraglutide safety and efficacy in patients with histology outcome did not find histology improvement in NASH NASH study) tested the use of liraglutide in NASH patients for patients supplemented with low-dose (1800 mg/day) or high-dose 48 weeks using histological endpoints.62 Resolution of definite (> 2700 mg/day) n-3 PUFA.11,73 NASH patients with diabetes NASH was achieved in nine of 23 (39%) patients who received also failed to show histology improvement after PUFA liraglutide and two of 22 (9%) in those who received a placebo supplementation.74 (P = 0.019). Although the proportion of patients with improve- The optimal duration of supplementation and most effective ment in fibrosis was similar, fewer patients in the liraglutide group dose of n-3 PUFA have not been determined. It also remains un- had fibrosis progression (2/23 [9%] vs 8/22 [36%]; P = 0.04). In a clear what the optimal source of n-3 PUFA is, in terms of whole related mechanistic substudy, liraglutide improved insulin sensi- foods, that is, fish oil or purified product. One study used purified tivity in both liver and adipose tissue and reduced fasting docoxahexaenoic acid plus eicosapentaenoic acid at a dose of hepatic de novo lipogenesis.63 Liraglutide is associated with gas- 4 g/day and demonstrated a reduction of liver fat assessed by mag- trointestinal upset and may partly exert beneficial effects on netic resonance spectroscopy.75 There was no report on the ad- NAFLD by causing weight reduction. Recently, liraglutide has verse effects of n-3 PUFA supplementation.

Journal of Gastroenterology and Hepatology 33 (2018) 86–98 89 © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd Asia-Pacific NAFLD guidelines S Chitturi et al.

Liver supplements. Silymarin may be useful for the treatment several retrospective and prospective observational cohort studies of NASH, but the optimal dose and duration requires further have demonstrated bariatric surgery often improves and even studies. completely resolves NASH.98–100 In recent systemic reviews and Silymarin, which is derived from the milk thistle plant Silybum meta-analyses,101–103 most studies report that > 75% of patients marianum, is a complex mixture of six major flavonolignans had no evidence of steatosis after weight loss surgery.101 Fourteen (silybins A and B, isosilybins A and B, silychristin, and studies have evaluated the effects of bariatric surgery on NASH; silydianin), as well as other minor polyphenolic compounds.76 all of them showed improvements in ballooning and lobular in- Several clinical trials have suggested that silymarin may be useful flammation. In patients with NAFLD, regression of fibrosis is pos- for the treatment of NAFLD.77–82 In a randomized, double- sible when at least 10% of body weight is lost. Among 18 studies blinded, placebo-controlled study on patients with biopsy-proven that describe postoperative fibrosis score on liver biopsy, 16 (89%) NASH, silymarin dosage of 700 mg three times daily for 48 weeks studies showed regression of fibrosis.101 However, a Cochrane resulted in significantly higher percentage of fibrosis reduction review104 concluded that the current lack of randomized clinical compared with placebo (22.4% vs 6.0%, P = 0.023).83 The dosage studies prevents a definitive assessment of the benefits and harms of 700 mg three times daily was safe and well tolerated, consistent of bariatric surgery as a therapeutic approach for patients with with that reported previously and was chosen to provide the NASH. highest likelihood of finding a therapeutic effect in the study. Until the last two decades, bariatric surgery conferred high risks Silymarin may also have beneficial effects on other components of complications, including steatohepatitis and liver failure from of the metabolic syndrome.84–86 jejunoileal bypass surgery. However, recent reviews and meta- analyses of 161 756 patients receiving bariatric surgery in USA describe an overall mortality of 0.22% and 30-day morbidity of The use of statins in non-alcoholic fatty liver 9.8%.105 Furthermore, the mortality and morbidity rate of laparo- disease patients. A systematic review has described the rel- scopic Roux-Y gastric bypass is similar to laparoscopic cholecys- ative safety of statin use, that is, liver failure notification rate to tectomy.106 Weingarten et al.107 reported on 340 patients who regulatory authorities of 1 million person-years and fewer underwent laparoscopic bariatric operations and had intraoperative hepatobiliary adverse events with statins compared with placebo liver biopsies. The complication rate did not differ significantly in RCTs involving patients with liver disease.87 A recent Cochrane across NASH categories. However, surgery for individuals with review, which included two RCTs with small patient populations established cirrhosis caused by NAFLD is associated with higher and a high risk of bias, showed statins improved transaminase perioperative risk. A recent review reported an overall operative levels and sonographic findings, but liver-related morbidity and morbidity in cirrhosis of 21%, with 6.6% risk of liver decompen- mortality were not reported. Despite the low quality of the evi- sation and 2.5% late surgery-related mortality rate patients108 dence, this review concluded that statin use in NAFLD may be jus- where the majority of these patients are Child–Pugh class A. The tified because they may prevent the adverse outcomes of operative mortality rate is also significantly higher in decompen- conditions related to NASH.88,89 A more recent review underlines sated cirrhosis than those with compensated state (16.3% and the safety of statin use in patients with NAFLD including those 0.9%, respectively).109 with slightly elevated alanine transaminases, that is, < 3× upper Non-alcoholic fatty liver disease is present in 65% to 90% of limit of normal and, their value in reducing the associated cardio- 90 bariatric surgery patients, and up to three quarters of these pa- vascular morbidity in this population. Experts have recom- – tients suffer from NASH.110 112 The role of screening is not mended that mild to modest increases in liver enzymes are not established for patients with NAFLD and NASH.113 Most pa- contraindications to either initiating or continuing statin use in tients with morbid obesity have NAFLD, and the surgical plan other chronic liver diseases, such as uncomplicated chronic hepa- will seldom be altered depending on the presence of NASH or titis B (CHB) and C, or in compensated liver cirrhosis. There are simple steatosis. However, if patients are known to have cirrhosis fragmentary data that statin use may reduce risk of HCC (among at the time of referral for consideration of bariatric surgery, the other malignancies), but this aspect requires further directed study. cause of cirrhosis should be elucidated and patients evaluated However, routine prescription of a statin is not recommended in – for hepatic function and presence of portal hypertension. Specif- patients with decompensated cirrhosis and acute liver failure.91 95 ically, they should undergo an upper endoscopy, looking for varices and/or portal gastropathy. Computed tomography can be Bariatric surgery. Non-alcoholic fatty liver disease often useful in detecting intraabdominal varices (and patent umbilical accompanies obesity and its complications, including T2DM, vein) not seen endoscopically and can reveal the presence of clin- obstructive sleep apnoea, gastroesophageal reflux disease, and ically indeterminable ascites and splenomegaly. Overall, the metabolic syndrome. Weight loss can be a highly effective literature suggests that in patients with well compensated state intervention for some of these diseases. Thus, bariatric surgery (Child–Pugh class A) without evidence of portal hypertension, is currently the recommended treatment in T2DM patients with bariatric surgery will result it slightly higher but acceptable mor- classes II and III obesity.96 The International Federation of Sur- bidity and mortality. This will delay progression of liver disease gery for Obesity Asia–Pacific Chapter had published a consensus to decompensation and also increase the candidacy for liver statement in 2011 that Asian patients should consider bariatric transplantation.114 surgery among their treatment options for metabolic syndrome and T2DM if their body mass index (BMI) > 30 kg/m2.97 Although there is a lack of RCTs comparing the effects of bar- Liver transplantation. In the USA, NASH is now the sec- iatric surgery with any other interventions on NAFLD or NASH, ond most common indication for liver transplantation and is the

90 Journal of Gastroenterology and Hepatology 33 (2018) 86–98 © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd S Chitturi et al. Asia-Pacific NAFLD guidelines most rapidly growing indication for liver transplantation in pa- NAFLD–HCC was mostly detected by outside surveillance. It tients with HCC.115–117 The indications for liver transplantation was larger and showed more of an infiltrative pattern at the time in NASH cirrhosis and HCC are the same as those for other eti- of diagnosis. Cirrhosis was present in only about 50% of patients ologies of liver disease.118 Overall survival rates after liver trans- with NAFLD–HCC.136–143 These patients had a similar recurrence plantation in patients with NASH are also the same as those for rate and survival rate compared with those with other etiology (3- other indications, but patients with NASH are more likely to year survival rate: 70–80%).137,139–141 However, HCC in NASH is die post-transplant because of CVD and chronic kidney dis- difficult to evaluate because histological diagnosis is required for ease.119,120 This is related to the fact that patients with NASH the diagnosis of NASH, which can lead to selection bias. Further- are usually older and are complicated by metabolic risk factors more, in end stage, the characteristic features of NASH disappear such as obesity and diabetes mellitus predisposing them to in- (i.e. burned-out NASH), and a diagnosis of NASH can no longer creased CVD and chronic kidney disease.115 Because of the risk be made. There are no special treatments for liver cancer based of prolonged ventilation, poor wound healing, higher rate of pri- on NASH/NAFLD. It should be treated according to the HCC mary graft non-function, and increased infectious complications, guidelines.144–147 patients with severe obesity (BMI > 40 kg/m2) and NASH cirrhosis may even be considered unfit for liver transplantation un- Recommendation Statements less efforts are made preoperatively to reduce body weight with individualized plans of lifestyle modifications.121,122 In 7.1 Lifestyle intervention programs can achieve reduction in liver exceptional circumstances, simultaneous bariatric and liver trans- fat content, resolution of steatohepatitis in all patients, as well as plantation surgery has also been performed in patients with reduction in liver fibrosis. (A1) NASH cirrhosis and obesity.123 Similar to obesity, patients with NASH and diabetes mellitus with poor glycemic control are at in- 7.2 A multidisciplinary approach to management is important to creased postoperative risk for infections, CVD, and acute cellular ensure motivation and continued participation in intervention pro- rejection. Hence, a thorough evaluation for diabetes and good grams. (B2) glycemic control is essential for good postoperative outcome in such patients.124 Because patients with NASH cirrhosis are at in- 7.3 Vitamin E may improve serum aminotransferases and liver his- creased risk for CVD that could be responsible for higher opera- tology in non-cirrhotic non-diabetic NASH adults but further stud- tive and postoperative mortality, a detailed cardiovascular ies are needed before firm recommendations can be made. (A2) assessment is a must for patients with NASH cirrhosis prior to liver transplantation.125 Even though recurrent NASH and severe 7.4 Pioglitazone cannot be recommended for general use in pa- fibrosis occur infrequently, the risk of recurrence of NAFLD in tients with NASH but could be considered for short-term use in pa- patients with NASH cirrhosis undergoing liver transplantation tients with pre-diabetes or type 2 diabetes. Careful assessment may approach 100% at 5 years.126 NAFLD can even develop should be made of co-morbid conditions (osteoporosis, cardiac de novo in patients undergoing liver transplantation for other eti- function) that may influence suitability of this agent in these pa- ologies because of the post-transplant metabolic syndrome related tients. (B2) to immunosuppression and multiple other factors.127 The treatment of post-liver transplantation NAFLD/NASH is largely with 7.5 The safety of pioglitazone in patients with cirrhosis has not lifestyle modifications with no data on the use of pioglitazone or been adequately established. Therefore, pioglitazone should be vitamin E. Management of post-transplant metabolic syndrome used with caution in cirrhotic patients (C2) would require limited use of calcineurin inhibitors and steroids and bariatric surgery in exceptional patients with severe 7.6 Pentoxifylline is not recommended as a treatment for obesity.128,129 NAFLD/NASH. (B2)

7.7 Metformin does not have direct effect on the histology of Management of non-alcoholic steatohepatitis- NASH. However, its other benefits are well documented. Metfor- related hepatocellular carcinoma min should remain the first-line anti-diabetic agent in patients with T2DM. (A1) Treatment choice and outcomes: any difference from hepatocellular carcinoma of other etiologies? Non-alcoholic 7.8 Liraglutide reduces cardiovascular complications and possibly fatty liver disease increases the risk of HCC and intrahepatic improves NASH. It may be considered in diabetic patients with cholangiocarcinoma.130–132 Obesity and diabetes, which are the NAFLD/NASH. However, its use in non-diabetic patients cannot main causes of NAFLD, have also been revealed as risk factors be recommended until more definitive data becomes available. (B2) for liver cancer by clinical and experimental studies. A synergistic effect of NAFLD, obesity, and diabetes may play a role in the de- 7.9 There is insufficient data to support the use of DPP-4 inhibitors velopment of liver cancer. As with other liver diseases, advanced as a treatment for NASH. (C2) fibrosis and cirrhosis are the most important risk factors for HCC.133–135 In addition, advanced age and male sex also increase 7.10 Obeticholic acid may improve NASH and fibrosis, but the risk of HCC. results observed in the Japanese population are inconsistent. As Compared with HCC of other etiology, HCC in patients with well, it also causes pruritus and atherogenic lipid profile. Until NAFLD is complicated by diabetes, hypertension, and CVDs. further information from the phase 3 study is available,

Journal of Gastroenterology and Hepatology 33 (2018) 86–98 91 © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd Asia-Pacific NAFLD guidelines S Chitturi et al. off-label use of obeticholic acid in NASH patients cannot be rec- randomized trial with 8 weeks of Lactobacillus GG reported a sig- ommended. (B2) nificant improvement in serum ALT, but not in liver ultrasound assessment.153 7.11 n-3 polyunsaturated fatty acids may reduce liver fat and improve blood lipid profile, but do not appear to have beneficial ef- Omega-3 fatty acids. Data regarding the effect of n-3 PUFAs fects on liver histology. (B2) on NAFLD are inconsistent.154 An RCT reported docosahexaenoic acid supplementation might decrease liver fat 7.12 When indicated, statins may be administered to patients with and increased insulin sensitivity in children.155 Another small trial NAFLD who have mild elevation of transaminases or compen- by Janczyk et al.156 found no effect of n-3 fish oil in either liver sated cirrhosis. (A1) steatosis or serum ALT. 7.13 Bariatric surgery can improve the histology of NASH and reduce long-term mortality, but its use should be limited to patients Cysteamine bitartrate delayed release. Glutathione is a ma- with class II obesity (BMI >32.5 kg/m2 in Asians and 35 kg/m2 in jor hepatocellular anti-oxidant. Cysteamine is a small molecule Caucasians). Its effect on improving liver-related complications is that can be taken up into cells and facilitates glutathione synthesis. as yet unproven but it may reduce overall mortality through its ef- A recent RCT of 169 children with NAFLD reported that cyste- fect on cardiovascular factors. (B1) amine bitartrate delayed release improved serum ALT, but not liver histology over 52 weeks.157 7.14 Lifestyle management should be offered before and after liver transplantation in patients with NASH-related end-stage liver dis- Fatty liver in patients with viral hepatitis ease. (B2) Prevalence and significance of hepatitis C virus-associated Special groups non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Non-alcoholic fatty liver disease or steatosis Children and adolescents. The management of NAFLD occurs commonly (around 50%) in patients with hepatitis C virus in children consists of treating liver disease itself as well as comor- (HCV) infection, whereas NASH can be documented in 4–10% of bidities such as obesity, hyperlipidemia, insulin resistance, T2DM, HCV-infected subjects.158–160 For the majority of patients infected and CVD. No pharmacologic treatment has yet been shown to be with HCV genotype non-3, steatosis is usually associated with the effective for NASH in children. presence of metabolic derangement and insulin resistance and is called “metabolic steatosis.” HCV genotype 3 infection itself may directly influence fat deposition in the liver, which is called Diet and lifestyle modification. Lifestyle modification is the “viral steatosis”; accordingly, HCV genotype 3 infection is associ- mainstay treatment for NAFLD in children. In the meantime, it – ated with the highest prevalence of steatosis.161 163 Genetic back- also improves the comorbidities. However, it is very difficult to ground of the hosts has been found to predispose patients to the achieve sustained lifestyle change, especially in children. development of steatosis.164 Irrespective of insulin resistance, In adults, moderate weight loss of 7–10% was associated with HCV-associated NAFLD contributes to the progression of under- reduced liver fat, NASH resolution, and even reduction of 148 lying liver fibrosis and the development of HCC by the accelera- fibrosis. However, the optimal lifestyle intervention for children – tion of liver necroinflammation and oxidative stress.165 167 is not well defined. Nobili et al.149 tested the effectiveness of 1-year Extrahepatically, NAFLD is associated with the presence of meta- lifestyle modification in 84 obese Italy children with biopsy-proven bolic syndrome, T2DM, and atherosclerosis.168 From the thera- NAFLD. Overall, patients losing 5% or more of body weight had peutic point of view, HCV-related metabolic steatosis may improvements in alanine aminotransferase (ALT) levels. Another – impair the response to interferon-based therapy,169 172 whereas pediatric study from Italy showed 2-kg weight loss could achieve genotype 3-associated viral steatosis was found to decrease the re- a decrease in ALT from 54 to 37 U/L and hepatic fat fraction from sponse to new oral direct antiviral agents.173 In summary, NAFLD 15.2% to 6.4% within 1 year.150 occurs commonly in patients with HCV infection, which in certain genotype is induced by the virus itself. NAFLD significantly im- Vitamin E. Oxidative stress is a key mechanism of hepatocellular pacts progression of the liver disease, therapeutic response, and injury, so vitamin E would be expected to have some effect in the development of some extrahepatic CVDs. NAFLD. The Treatment of Nonalcoholic Fatty Liver Disease in Children trial reported a modest benefit of vitamin E in NAFLD Prevalence and significance of hepatitis B virus-associated in children by showing some improvement in ballooning degener- non-alcoholic fatty liver disease and non-alcoholic ation only.151 steatohepatitis. Hepatitis B virus (HBV) infection is a major etiology of chronic liver disease worldwide, and NAFLD has Probiotics. Gut dysbiosis has been known to play a key role in emerged as a common liver disorder in the general population. the pathogenesis of NAFLD, and probiotics seem to be a logic tar- Therefore, the number of patients with coexisting CHB and get to benefit NAFLD. In obese children, administration of NAFLD grows rapidly. Interestingly, patients with CHB were VSL#3, a mixture of eight probiotic strains, for 4 months de- found to have a lower evidence of NAFLD in comparison with creased steatosis and BMI, but not serum ALT.152 Another the general populations and subjects with chronic HCV

92 Journal of Gastroenterology and Hepatology 33 (2018) 86–98 © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd S Chitturi et al. Asia-Pacific NAFLD guidelines infection.174–177 Specifically, around 14–56% of patients with 5 Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L et al. chronic HBV infection had evidence of fatty liver. The mecha- Weight loss through lifestyle modification significantly reduces nism is possibly due to a lower frequency of dyslipidemia profile features of nonalcoholic steatohepatitis. Gastroenterology 2015; 149 – in patients with chronic HBV infection. Recent studies aimed to : 367 78.e5. 6 Thoma C, Day CP, Trenell MI. Lifestyle interventions for the explore the relationship between CHB and NAFLD from differ- treatment of non-alcoholic fatty liver disease in adults: a systematic ent aspects. review. J. Hepatol. 2012; 56: 255–66. Although numerous cross-links have been found between HBV 7 Golabi P, Locklear CT, Austin P et al. Effectiveness of exercise in infection and NAFLD pathogenesis, the association of HBV with hepatic fat mobilization in non-alcoholic fatty liver disease: metabolic syndrome, insulin resistance, and the risk of arterioscle- systematic review. World J. Gastroenterol. 2016; 22: 6318–27. rosis is still inconclusive.178 Notably, obesity, diabetes, and meta- 8 Jin YJ, Kim KM, Hwang S et al. Exercise and diet modification in bolic syndrome may accelerate the progression of liver disease in non-obese non-alcoholic fatty liver disease: analysis of biopsies of patients with chronic HBV infection and synergistically induce living liver donors. J. Gastroenterol. Hepatol. 2012; 27: 1341–7. cirrhosis or even hepatocellualr carcinoma development.179–182 9 Wong VW, Chan RS, Wong GL et al. Community-based lifestyle fi Recent prospective cohort studies further demonstrated that meta- modi cation programme for non-alcoholic fatty liver disease: a randomized controlled trial. J. Hepatol. 2013; 59: 536–42. bolic syndrome may increase the risk of cardiovascular events but 183 10 Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R et al. Long not hepatic events and death. Finally, from the therapeutic point term nutritional intake and the risk for non-alcoholic fatty liver of view, a recent review demonstrated that coexisting NAFLD did disease (NAFLD): a population based study. J. Hepatol. 2007; 47: not influence the response to oral nucleos(t)ide analogue or inter- 711–17. feron therapy.184 11 Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkier M, Group E-AS. No significant effects of ethyl-eicosapentanoic acid on Recommendation Statements histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology 2014; 147: 377–84 e1. 8.1 Until further data from clinical trials become available, no 12 Ryan MC, Itsiopoulos C, Thodis T et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with pharmacological treatment can be recommended for children and non-alcoholic fatty liver disease. J. Hepatol. 2013; 59: 138–43. adolescents with NAFLD/NASH. In this situation, lifestyle modi- 13 Sacks FM, Bray GA, Carey VJ et al. Comparison of weight-loss diets fi cation should be recommended. (B2) with different compositions of fat, protein, and carbohydrates. N. Engl. J. Med. 2009; 360: 859–73. 8.2 Hepatic steatosis occurs commonly in patients with hepatitis C 14 Adams LA, Lymp JF, St Sauver J et al. The natural history of virus (“HCV”) infection, and is associated with extrahepatic man- nonalcoholic fatty liver disease: a population-based cohort study. ifestations. HCV-associated steatosis contributes to the progres- Gastroenterology 2005; 129: 113–21. sion of underlying liver fibrosis and the development of 15 Wong VW, Wong GL, Yeung JC et al. Long-term clinical outcomes hepatocellular carcinoma, and may impair the response to after fatty liver screening in patients undergoing coronary angiogram: 63 – interferon-based therapy. (B2) a prospective cohort study. Hepatology 2016; : 754 63. 16 Garber CE, Blissmer B, Deschenes MR et al. American College of Sports Medicine position stand. Quantity and quality of exercise for 8.3 The prevalence of NAFLD in patients with HBV infection developing and maintaining cardiorespiratory, musculoskeletal, and appears to be lower than that in the general population. The pres- neuromotor fitness in apparently healthy adults: guidance for ence of metabolic syndrome may accelerate the progression of prescribing exercise. Med. Sci. Sports Exerc. 2011; 43: 1334–59. liver disease in patients with chronic HBV infection. 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