Community-based lifestyle modification programme for non-alcoholic fatty liver disease: A randomized controlled trial

Accepted Manuscript Community-based lifestyle modification programme for non-alcoholic fatty liv‐ er disease: A randomized controlled trial Vincent Wai-Sun Wong, Ruth Suk-Mei Chan, Grace Lai-Hung Wong, Bernice Ho-Ki Cheung, Winnie Chiu-Wing Chu, David Ka-Wai Yeung, Angel Mei-Ling Chim, Jennifer Wing-Yan Lai, Liz Sin Li, Mandy Man-Mei Sea, Francis KaLeung Chan, Joseph Jao-Yiu Sung, Jean Woo, Henry Lik-Yuen Chan PII: DOI: Reference:

S0168-8278(13)00266-3 http://dx.doi.org/10.1016/j.jhep.2013.04.013 JHEPAT 4673

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Journal of Hepatology

Received Date: Revised Date: Accepted Date:

21 February 2013 10 April 2013 15 April 2013

Please cite this article as: Wong, V.W-S., Chan, R.S-M., Wong, G.L-H., Cheung, B.H-K., Chu, W.C-W., Yeung, D.K-W., Chim, A.M-L., Lai, J.W-Y., Li, L.S., Sea, M.M-M., Chan, F.K-L., Sung, J.J-Y., Woo, J., Chan, H.L-Y., Community-based lifestyle modification programme for non-alcoholic fatty liver disease: A randomized controlled trial, Journal of Hepatology (2013), doi: http://dx.doi.org/10.1016/j.jhep.2013.04.013

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1 Community-based lifestyle modification programme for non-alcoholic fatty liver disease: A randomized controlled trial Running head: Lifestyle programme for fatty liver Clinical trial registration: ClinicalTrials.gov NCT00868933

Vincent Wai-Sun Wong1,2*, Ruth Suk-Mei Chan2,3*, Grace Lai-Hung Wong1,2, Bernice Ho-Ki Cheung2,3, Winnie Chiu-Wing Chu1,4, David Ka-Wai Yeung5, Angel Mei-Ling Chim1,2, Jennifer Wing-Yan Lai2, Liz Sin Li2, Mandy Man-Mei Sea2,3, Francis Ka-Leung Chan1,2, Joseph Jao-Yiu Sung1, Jean Woo2,3, Henry Lik-Yuen Chan1,2

1

Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong

2

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong

Kong 3

Centre for Nutritional Studies, The Chinese University of Hong Kong, Hong Kong

4

Department of Imaging and Interventional Radiology, The Chinese University of Hong

Kong, Hong Kong 5

Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong

* These authors contributed equally to this work.

2 Correspondance: Jean Woo, M.D. 9/F, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong Tel: +852 26323141

Fax: +852 26373852

E-mail: [email protected]

Henry Chan, M.D. 9/F, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong Tel: +852 26323593

Fax: +852 26373852

E-mail: [email protected]

Electronic word count: Abstract – 241, Full paper – 4998 Number of tables: 3 Number of figures: 3

List of abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; GI, glycaemic index; HDL, high density lipoprotein; 1H-MRS, proton-magnetic resonance spectroscopy; IHTG, intrahepatic triglyceride content; LDL, low density lipoprotein; NAFLD, non-alcoholic fatty liver disease

3 Conflict of interests: Vincent Wong, Grace Wong and Henry Chan have received paid lecture fees from Echosens.

Financial support: This study was supported in part by the Nutritional Research Foundation of the United Kingdom, the direct grant of the Chinese University of Hong Kong (ref 2011.1.025) and a grant from the Research Grants Council of the Hong Kong SAR (Project No. SEG CUHK_02).

4 ABSTRACT Background & Aims: Healthy lifestyle is the most important management of nonalcoholic fatty liver disease (NAFLD). This study aimed to assess the efficacy of a community-based lifestyle modification programme in the remission of NAFLD. Methods: This was a parallel group, superiority, randomized controlled trial. 154 adults with NAFLD identified during population screening were randomized to participate in a dietitian-led lifestyle modification programme at 2 community centres or receive usual care for 12 months. The primary outcome was remission of NAFLD at month 12 as evidenced by intrahepatic triglyceride content (IHTG) of less than 5% by protonmagnetic resonance spectroscopy. Results: 74 patients in the intervention group and 71 patients in the control group completed all study assessments. In an intention-to-treat analysis of all 154 patients, 64% of the patients in the intervention group and 20% in the control group achieved remission of NAFLD (difference between groups 44%; 95% CI 30-58%; P<0.001). The mean (SD) changes in IHTG from baseline to month 12 were -6.7% (6.1%) in the intervention group and -2.1% (6.4%) in the control group (P<0.001). Body weight decreased by 5.6 (4.4) kg and 0.6 (2.5) kg in the two groups, respectively (P<0.001). While 97% of patients with weight loss of more than 10% had remission of NAFLD, 41% of those with weight loss of 3.0-4.9% could also achieve the primary outcome. Conclusion: The community-based lifestyle modification programme is effective in reducing and normalizing liver fat in NAFLD patients.

5 Keywords: Obesity; weight loss; non-alcoholic steatohepatitis; transient elastography; magnetic resonance spectroscopy

6 INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) affects 15-40% of the general adult population and is the most common cause of abnormal liver biochemistry worldwide [1, 2]. Some patients with NAFLD run a progressive clinical course and may develop cirrhosis and hepatocellular carcinoma [3-6].

Lifestyle modification is the cornerstone of the management of NAFLD [7]. Weight reduction by dietary intervention and/or exercise is associated with decrease in liver enzymes [8-11], reduced liver fat [12-15], and improvement in liver histology [16, 17]. However, 2 important questions remain unanswered. First, the majority of NAFLD patients are seen at the primary care setting. Reported intervention programmes were invariably conducted in expert centres. The implementation and efficacy of lifestyle modification programmes at the community setting are unclear. Second, many reported interventions involved tightly controlled diet over short periods ranging from several weeks to months. It is unlikely that patients can adhere to such diets for long. The optimal intervention with good efficacy and sustainability for patients with NAFLD is currently unknown.

This study tested the hypothesis that a community-based lifestyle modification programme is superior to usual care in normalizing hepatic steatosis in patients with NAFLD.

7 PATIENTS AND METHODS Trial design This was a parallel group, superiority, single-blind randomized controlled trial comparing a community-based lifestyle modification programme with usual care in NAFLD patients.

Study population NAFLD patients were recruited from a population screening project in Hong Kong. Details of the project have been described previously [2, 18]. In brief, a list of local citizens was randomly generated from the government census database. They were invited to undergo screening with proton-magnetic resonance spectroscopy (1H-MRS).

Subjects found to have NAFLD were then invited to enter this intervention trial. The specific inclusion criteria were age 18 to 70 years; fatty liver by 1H-MRS, defined as intrahepatic triglyceride content (IHTG) of 5% or above; and plasma alanine aminotransferase (ALT) above 30 IU/l in men and 19 IU/l in women. Subjects tested positive for hepatitis B surface antigen or anti-hepatitis C virus antibody, or anti-nuclear antibody titer above 1/160 were excluded. Other exclusion criteria were alcohol consumption above 20 g per day in men and 10 g per day in women; liver decompensation; and terminal illness and cancer including hepatocellular carcinoma. All patients provided informed written consent. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, was approved by the Clinical Research Ethics Committee of The Chinese University of Hong Kong, and was registered at ClinicalTrials.gov (NCT00868933).

8

Trial procedures Patients fulfilling the inclusion and exclusion criteria were randomized in 1:1 ratio to participate in the lifestyle modification programme or receive usual care. Randomization was performed through the use of a computer-generated list of random numbers in blocks of 6 by a nursing officer. Treatment assignments were concealed in consecutivelynumbered sealed envelopes, which were opened sequentially upon patient enrollment. Clinicians and radiographers who analyzed 1H-MRS results were blinded to the treatment assignment.

Intervention group Patients randomized to the intervention group participated in a dietitian-led lifestyle modification programme for 12 months. All patients received individual education. The programme was held at 2 urban centres that are open to the public for the management of obesity and related disorders. The programme is based on a strategy of increasing energy expenditure and reducing caloric intake using lifestyle behavioral change to achieve longlasting impact. The patients attended dietary consultation sessions weekly in the first 4 months, and monthly in the following 8 months. At the first session (about 1 hour), the dietitian carried out a complete behavioral assessment, covering important areas such as the patient’s current eating and lifestyle patterns, specific eating-related behaviors, knowledge of risks associated with current eating patterns, and concerns and feelings about specific lifestyle changes. The dietitian also discussed the expected duration and specific dietary and lifestyle advices to achieve a desirable weight status with the patients.

9

In the follow-up sessions (about 20 minutes), the dietitian reviewed the patient’s dietary practice and provided recommendations. Each patient was given an individualized menu plan. The dietary component and portion sizes of the menu plan were based on the recommendations of the American Dietetic Association [19]. A varied balanced diet with an emphasis on fruit and vegetables, and moderate-carbohydrate, low-fat, low-glycaemic index (GI) and low-calorific products in appropriate portions was encouraged. The diet resulted in a relative increase in energy consumption from proteins, which also promoted satiety. Each patient was provided with two booklets, one for food portion size exchange and tips for eating out, and another listing the low-GI food options and meal plans (GI <55). Moreover, techniques for coping at-risk situations such as parties and festival celebrations were taught. Recipes were also provided to the patients to encourage healthy cooking. Adherence to dietary intervention was assessed by calculating the percentage attendance to the intervention sessions and evaluating the dietary intakes and meal patterns using a weekly food record.

Besides, patients were encouraged to see an exercise instructor at least once during the lifestyle modification programme. During the first exercise consultation (about 30 minutes), the exercise instructor reviewed the patient’s medical history and exercise habits, and designed a suitable exercise regime for the patient. The patients were first instructed to do moderate intensity aerobic exercise for 30 minutes 3 to 5 days a week and encouraged to increase daily physical activities. During subsequent appointments, the exercise instructor evaluated the patient’s exercise progress on aerobic exercise and

10 stretching during follow-ups. When patients were able to develop a routine exercise habit, they were instructed to perform resistance training to increase their muscle endurance and strength for better aerobic performance and liver fat reduction [20]. The intensity of exercise was gradually increased to 30 minutes every day. The target was a reduction of body mass index (BMI) towards 23 kg/m2.

Control group Patients in the control group received routine care at the medical clinic of the Prince of Wales Hospital, Hong Kong. At baseline, a clinician explained the laboratory test results and the natural history of NAFLD to the patients. The patients were encouraged to reduce carbohydrate and fat intake, and to exercise for at least 3 times per week, 30 minutes per session.

Follow-up assessments The patients attended the clinic at months 3, 6, 9 and 12 for metabolic assessment, and received further advice from a clinician at months 6 and 12. During each visit, new symptoms and drug intake were monitored by history and territory-wide computer prescription record. Anthropometric measurements, liver biochemistry, fasting glucose and lipids were assessed. BMI was calculated as body weight (kg) divided by body height (m) squared. Waist circumference was measured at a level midway between the lower rib margin and iliac crest with the tape all around the body in the horizontal position. Physical activities were recorded as the total duration of active exercise (minutes) per week.

11

At baseline and month 12, 1H-MRS and liver stiffness measurement were performed to assess hepatic steatosis and fibrosis, respectively. IHTG was measured by 1H-MRS using a whole-body 3.0T scanner with a single voxel point-resolved spectroscopy sequence and an echo time of 40 ms and repetition time of 5000 ms as described previously [21]. Liver stiffness measurement was performed by transient elastography (Fibroscan, Echosens, Paris, France) by experienced operators who had performed at least 50 measurements prior to this study according to the manufacturer’s instructions [22]. Ten liver stiffness measurements were performed on each patient. The median of 10 measurements reflected the liver stiffness, while the interquartile range was used to estimate the variability of measurements. Cases with less than 10 successful acquisitions or an interquartile rangeto-median ratio of 0.3 or more were considered to have unreliable measurements and were excluded from analysis.

Study outcomes The primary outcome was remission of NAFLD at month 12 as evidenced by IHTG of less than 5% by 1H-MRS. Secondary outcomes were reduction in IHTG and changes in liver stiffness by transient elastography, anthropometric measurements, liver biochemistry, fasting glucose and lipids.

Statistical analysis A large observational study in Japan showed that 16% of patients had spontaneous remission of NAFLD in 1 to 2 years [23]. Assuming that 45% of patients in the

12 intervention group and 20% of patients in the control group would have remission of NAFLD, a sample size of 62 patients per group would achieve 80% power to detect the difference at a 5% significance level using the chi-squared test. Assuming that 20% of the patients would be lost to follow-up, a total sample size of 155 patients was required.

Continuous variables were expressed in mean (SD) unless otherwise specified and were compared between the treatment groups using unpaired t test. Categorical variables were compared using χ2 test or Fisher exact test as appropriate. Intention-to-treat analysis was performed for each outcome. Missing values were treated using the last-observationcarried-forward method and were considered failure for that outcome. A two-sided P value of less than 5% was taken as statistically significant. All statistical tests were performed with IBM SPSS Statistics version 20 (IBM Corporation, Armonk, NY).

13 RESULTS Study subjects Of 1069 people who underwent population screening from May 2008 to September 2010, 251 had NAFLD, of which 154 had abnormal ALT level and consented to join the trial (Fig. 1). 77 patients were randomized to the lifestyle modification programme and 77 received usual care. Three patients in the intervention group and 6 in the control group were lost to follow-up, but all randomized patients were included in the intention-to-treat analysis. The two groups were well-matched in demographic characteristics, clinical and laboratory data, IHTG and liver stiffness measurements (Table 1).

64 (83%) patients in the intervention group attended more than 80% of the dietary consultation sessions. 65 (84%) patients in the intervention group attended exercise consultation sessions. At baseline, patients in the intervention group and control group exercised for 56 (SD 49) minutes and 45 (SD 52) minutes per week, respectively (P=0.19). At month 12, the total duration of exercise per week in the two groups increased modestly to 62 (SD 56) and 58 (SD 60) minutes, respectively (P=0.63). During the study period, none of the patients were started on insulin sensitizers, weight loss agents, lipid lowering drugs, vitamin E and omega-3 supplements.

Primary outcome The primary outcome of remission of NAFLD at month 12 occurred in 49 of 77 (64%) patients in the intervention group and 15 of 77 (20%) patients in the control group (difference between groups 44%; 95% CI 30-58%; P<0.001) (Table 2). By univariate

14 analysis, lifestyle intervention, reduced body weight, reduced waist circumference and reduced total cholesterol were associated with remission of NAFLD (Table 3). By multivariate analysis, only reduction in body weight remained as an independent factor associated with remission of NAFLD, while the adjusted odds ratio for lifestyle intervention decreased from 7.23 to 2.31 (95% CI 0.92-5.79; P=0.074), indicating that the effect of lifestyle intervention was largely mediated through weight reduction.

Secondary outcomes At month 12, IHTG was significantly lower in the intervention group than the control group (mean difference 4.5%; 95% CI 2.5-6.5%; P<0.001) (Table 2). The mean reduction in IHTG from baseline to month 12 was 6.6% (SD 6.1%) in the intervention group and 2.1% (SD 6.4%) in the control group (mean difference 4.6%; 95% CI 2.6-6.6%; P<0.001).

In addition, patients in the intervention group had greater reduction in body weight, BMI and waist circumference (Table 2). A difference in weight loss between the two groups was significant by month 3 and was maintained through month 12 (Fig. 2). 59 (77%) patients in the intervention group and 23 (30%) patients in the control group had weight loss of 3% or more (difference between groups 47%; 95% CI 33-61%; P<0.001). 30 (39%) patients in the intervention group and no patient in the control group had weight loss of 10% or more (difference between groups 39%; 95% CI 28-50%; P<0.001).

15 Weight loss was associated with remission of NAFLD in a dose-dependent manner in the entire population (Fig. 3). While only 9 of 72 patients (13%; 95% CI 5-20%) with less than 3% reduction in body weight had remission of NAFLD, 29 of 30 patients (97%; 95% CI 90-100%) with more than 10% reduction in body weight could achieve the primary outcome. Moreover, more than 40% of patients with at least 3% reduction in body weight had remission of NAFLD.

Furthermore, the intervention group had greater reduction in ALT and liver stiffness, and lower low density lipoprotein-cholesterol levels at month 12 than the control group (Table 2).

16 DISCUSSION In this randomized controlled trial, a community-based lifestyle modification programme resulted in remission of NAFLD in the majority of patients. The efficacy on weight reduction was sustainable at 1 year. Although the chance of NAFLD remission increased with the degree of weight loss in a dose-response fashion, over 40% of patients with weight loss of as little as 3.0-4.9% of the baseline body weight also achieved remission of NAFLD.

In a randomized controlled trial of 31 overweight or obese subjects with biopsy-proven non-alcoholic steatohepatitis, a lifestyle intervention programme using a combination of diet, exercise and behavioral modification resulted in greater reduction in histological hepatic steatosis and NAFLD activity score [17]. While this trial was unique in using histological endpoints, the sample size was small due to the difficulty in persuading patients to undergo repeated liver biopsies. On the other hand, studies using liver enzymes and/or liver fat as the study outcomes are unable to evaluate the severity of liver disease [8-15]. In particular, ALT level has been shown to correlate poorly with liver histology in NAFLD patients [24]. With new technological development, it is now possible to accurately evaluate the liver using non-invasive tests. 1H-MRS can accurately quantify and monitor IHTG [25], and transient elastography is an accurate and reproducible test for liver fibrosis [22]. By adopting these new tests, our study clearly demonstrates that lifestyle intervention can not only reduce liver fat but also result in remission of NAFLD.

17 Although the patients in our study had relatively mild disease, they represent the spectrum of patients who are commonly seen at the primary care setting. In our study, all patients were recruited from the community and the dietary intervention was performed at 2 community centres. Over 80% of the patients in the intervention group could adhere to the programme. This compares favorably to other intervention trials, in which up to 50% of patients may refuse to participate or are lost to follow-up [8-15, 17]. One reason for the high response rate was because our subjects had already participated in the population screening programme and were therefore more ready to join further activities. The high adherence rate was also achieved through the rapport between the dietitians and patients and our flexible arrangements. The dietitians’ capability of providing professional information and psychological support was an important element of this lifestyle intervention for good adherence and helping patients overcome barriers for lifestyle and behavioural change [26, 27]. To cater for patient needs, some intervention sessions were arranged after office hours and during weekends.

Compared to previous studies, our study had relatively large sample size and was conducted in the community setting where most NAFLD patients are found. Nevertheless, the study has several limitations. First, as liver biopsy was not performed, we could not evaluate some NAFLD features such as necroinflammation. The performance of transient elastography in monitoring fibrosis in NAFLD patients is also unknown. Second, the nature of intervention made blinding of patients impossible. Unmeasured changes other than dietary and exercise pattern might have contributed to the remission of NAFLD. Finally, our patients had relatively low BMI compared to those reported in Western

18 studies. This was the result of recruitment from the general population and the different definition of obesity in the Asian population. Asians generally develop visceral obesity at a lower BMI. Future studies are required to determine to effect of lifestyle intervention on a more obese population.

In conclusion, a community-based lifestyle modification programme is effective in reducing and normalizing liver fat in NAFLD patients. While the effect is proportional to the degree of weight loss, a substantial proportion of patients with weight loss of 3% or more have remission of NAFLD.

19 Acknowledgements We would like to thank Cheong-Chun Chan from Jockey Club School of Public Health and Primary Care for dietary data entry and analysis. We also thank the following medical and nursing students for their help in clinical data collection and entry: YikChing Hung, Queenie Lau, Kam-Ho Lui, Long-Hei Siu, Kelvin Wan, Ho-On Wong and Ronald Wong.

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24 Table 1. Baseline characteristics Intervention group

Control group

(n=77)

(n=77)

Age (years)

51 (9)

51 (9)

Male gender

41 (52%)

31 (41%)

Body weight (kg)

70.6 (11.9)

68.4 (9.8)

BMI (kg/m2)

25.5 (3.9)

25.3 (3.2)

Male

24.9 (3.4)

25.1 (2.2)

Female

26.1 (4.2)

25.4 (3.7)

89 (9)

88 (8)

Male

89 (9)

90 (5)

Female

89 (8)

87 (9)

0.91 (0.05)

0.90 (0.06)

Male

0.92 (0.06)

0.92 (0.05)

Female

0.91 (0.05)

0.89 (0.07)

Systolic blood pressure (mmHg)

136 (22)

136 (21)

Diastolic blood pressure (mmHg)

87 (13)

86 (13)

ALT (IU/l)

43 (28)

40 (23)

AST (IU/l)

26 (12)

25 (12)

0.71 (0.31)

0.70 (0.21)

66 (25)

66 (19)

Demographics and baseline measurements

Waist circumference (cm)

Waist-to-hip ratio

AST/ALT ratio Alkaline phosphatase (IU/l)

25 Fasting glucose (mmol/l)

5.4 (1.1)

5.6 (1.5)

Total cholesterol (mmol/l)

5.2 (1.0)

5.5 (1.1)

HDL-cholesterol (mmol/l)

1.3 (0.3)

1.3 (0.3)

LDL-cholesterol (mmol/l)

3.2 (1.1)

3.3 (0.9)

Triglycerides (mmol/l)

1.8 (1.4)

2.2 (2.4)

IHTG (%)

12.3 (6.6)

12.2 (6.8)

Liver stiffness (kPa)*

5.1 (1.8)

5.0 (1.7)

4 (5%)

8 (10%)

23 (30%)

21 (27%)

Current smoking

6 (8%)

11 (14%)

Median (range) alcohol

0 (0-50)

0 (0-60)

Metformin

2 (3%)

5 (7%)

Sulphonylurea

1 (1%)

4 (5%)

Thiazolidinedione

0

0

Insulin

0

0

Statin

3 (4%)

6 (8%)

Medical history Type 2 diabetes Hypertension

consumption (g per week) Drug history

Values are mean (SD) or numbers (percentages) unless otherwise specified *Included 65 patients in the intervention group and 73 patients in the control group with reliable liver stiffness measurement

26 ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; HDL, high density lipoprotein; IHTG, intrahepatic triglyceride content; LDL, low density lipoprotein

 

Table 2. Study outcomes and metabolic changes from baseline to month 12 Variable

IHTG (%)

Intervention group

Control group

(n=77)

(n=77)

Baseline

Month 12

Baseline

Month12

12.3 (6.6)

5.5 (5.9)

12.2 (6.8)

10.1 (6.7)

Change in IHTG (%) Liver stiffness (kPa)

-6.7 (6.1) 5.1 (1.8)

Change in liver stiffness (kPa) Body weight (kg)

70.6 (11.9)

24.0 (5.7)

89 (9)

68.4 (9.8)

25.3 (3.2)

86 (9)

88 (8)

67.8 (9.9)

25.4 (4.5)

0.086 0.014

89 (8)

0.90 (0.06)

0.11 <0.001

1 (5) 0.90 (0.06)

0.040 0.016

0.2 (3.8)

-3 (6) 0.91 (0.05)

5.2 (1.9)

-0.6 (2.5)

-1.5 (4.5)

Change in waist circumference (cm) Waist-to-hip ratio

65.0 (11.0)

25.5 (3.9)

5.0 (1.7)

<0.001 <0.001

0.2 (1.7)

-5.6 (4.4)

Change in BMI (kg/m2) Waist circumference (cm)

4.6 (1.4) -0.5 (1.4)

Change in body weight (kg) BMI (kg/m2)

-2.1 (6.4)

P

0.040 <0.001

0.91 (0.06)

0.39

 

Change in waist-to-hip ratio ALT (IU/l)

0 (0.06) 43 (28)

Change in ALT (IU/l) AST (IU/l)

26 (12)

Change in triglycerides (mmol/l)

1.4 (0.3)

3.2 (1.1) -0.3 (1.0)

5.7 (1.3)

5.5 (1.1)

1.3 (0.3)

3.3 (0.9)

2.2 (2.4) -0.5 (2.1)

0.15 0.48

5.2 (0.9)

0.052 0.79

1.3 (0.3)

0.15 0.10

3.1 (0.8)

-0.2 (0.6) 1.5 (1.4)

-0.3 (1.5)

5.6 (1.5)

0.75 0.53

0 (0.2) 2.9 (0.8)

1.8 (1.4)

22 (8)

-0.3 (0.7)

0.1 (0.2)

Change in LDL-cholesterol (mmol/l) Triglycerides (mmol/l)

4.9 (0.9)

1.3 (0.3)

25 (12)

0.009 0.011

0.1 (1.3)

-0.3 (0.8)

Change in HDL-cholesterol (mmol/l) LDL-cholesterol (mmol/l)

5.4 (1.3)

5.2 (1.0)

33 (17)

-3 (11)

0 (0.5)

Change in total cholesterol (mmol/l) HDL-cholesterol (mmol/l)

22 (8)

5.4 (1.1)

40 (23)

0.11

-7 (19)

-4 (12)

Change in fasting glucose (mmol/l) Total cholesterol (mmol/l)

26 (13) -17 (30)

Change in AST (IU/l) Fasting glucose (mmol/l)

0 (0.06)

0.042 0.28

1.7 (1.0)

0.34 0.58

 

Resolution of NAFLD†

49 (64%)

15 (20%)

<0.001

ALT normalization‡

41 (53%)

19 (25%)

<0.001

Resolution of NAFLD and ALT

30 (39%)

5 (7%)

<0.001

normalization† Values are mean (SD) or numbers (percentages). P values refer to comparisons between the intervention and control groups for data at month 12 or changes from baseline to month 12. *Included 65 patients in the intervention group and 73 patients in the control group with reliable liver stiffness measurement †Resolution of NAFLD was defined as IHTG less than 5.0% at month 12 ‡ALT normalization was defined as ALT below 30 IU/l in men and 19 IU/l in women at month 12 ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; HDL, high density lipoprotein; IHTG, intrahepatic triglyceride content; LDL, low density lipoprotein

 

Table 3. Factors associated with remission of NAFLD Factors

Univariate analysis

Multivariate analysis

Odds ratio

95% CI

P

Adjusted odds ratio

95% CI

P

Lifestyle intervention

7.23

3.48-15.02

<0.001

2.31

0.92-5.79

0.074

Age

1.00

0.97-1.04

0.96

Male gender

0.95

0.50-1.80

0.87

Baseline body weight (kg)

0.99

0.96-1.02

0.58

Change in body weight (kg)

0.68

0.60-0.77

<0.001

0.72

0.62-0.85

<0.001

Baseline waist circumference (cm)

0.98

0.94-1.03

0.43

Change in waist circumference (cm)

0.85

0.79-0.92

<0.001

0.94

0.86-1.02

0.94

Baseline ALT (IU/l)

1.00

0.98-1.01

0.47

Change in ALT (IU/l)

0.99

0.98-1.01

0.25

Baseline fasting glucose (mmol/l)

0.87

0.66-1.15

0.34

Change in fasting glucose (mmol/l)

0.71

0.48-1.05

0.089

Baseline total cholesterol (mmol/l)

1.09

0.80-1.50

0.57

 

Change in total cholesterol (mmol/l)

0.63

0.40-1.00

0.048

Baseline HDL-cholesterol (mmol/l)

2.93

0.92-9.36

0.069

Change in HDL-cholesterol (mmol/l)

3.68

0.80-16.96

0.094

Baseline LDL-cholesterol (mmol/l)

1.20

0.86-1.68

0.28

Change in LDL-cholesterol (mmol/l)

0.62

0.39-1.01

0.055

Baseline triglycerides (mmol/l)

0.78

0.56-1.08

0.13

Change in triglycerides (mmol/l)

1.05

0.87-1.28

0.59

0.82

0.47-1.43

0.48

  Figure legends Fig. 1. Study flow diagram

Fig. 2. Mean changes in body weight over time in the intervention and control groups (P<0.001 for every time point from month 3 to month 12; error bars represent standard error of mean)

Fig. 3. Percentage of patients with remission of NAFLD according to the percentage of weight loss from baseline to month 12 (P<0.001 for trend)

Figure 1

People who underwent population screening (n=1069)

Excluded (n=915): Contraindications to magnetic resonance imaging (n=52) Failed magnetic resonance spectroscopy (n=1) No fatty liver (n=658) Hepatitis B infection (n=91) Hepatitis C infection (n=3) Significant alcohol consumption (n=13) Normal alanine aminotransferase (n=83) Refusal to consent (n=14)

NAFLD patients randomised (n=154)

Allocated to intervention group (n=77)

Allocated to control group (n=77)

Lost to follow-up and discontinued intervention due to tight schedule (n=2) and poor mobility (n=1)

Lost to follow-up and discontinued intervention due to tight schedule (n=6)

Analysed (n=77)

Analysed (n=77)

Figure 2

Intervention group

Control group

0

Change in body weight (kg)

-1 -2 -3 -4 -5 -6

-7 0

3

6 Months

9

12

Figure 3

97

% patients with resolution of NAFLD

100 80

60

60

50

41

40 20

13

0 <3.0%

3.0-4.9%

5.0-6.9%

7.0-9.9%

≥10.0%

Percentage of weight loss from baseline to month 12 n =

72

22

10

20

30