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There is no effective therapy for non-alcoholic fatty liver disease (NAFLD), although intensive calorie restriction is typically recommended but dietary adherence is an issue. Currently, there are no studies had been focusing the effect of Modified Alternate Day Calorie Restriction in NAFLD patient focusing on changes in liver steatosis and fibrosis.
Disease activity and progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) and cirrhosis can be highly variable, where 2-3% will eventually progress to end-stage liver diseases. With the rising prevalence of metabolic syndrome and obesity, NAFLD has become the most frequent form of chronic liver disease in the West but also in Asia.
There are good evidence that weight loss is effective in improving liver histology in NAFLD, for example, 31 obese patients with NASH was randomised into intensive lifestyle changes over 48 weeks versus structured basic education only, and the intensive lifestyle group showed significant improvements in steatosis, necrosis, and inflammation. Intense calorie restriction is the recommended form of dietary strategy for management of NAFLD. Even though such intense dietary strategy has proven to be effective, some patients find it difficult to adhere and maintain.
On the other hand, intermittent fasting achieves more consistent weight loss by improving adherence, as intermittent fasting only requires calorie restriction every other day compared to conventional form of daily calorie restriction. Alternate day calorie restriction can be divided into two components, a 'feed day' and a 'fast day' where food is consumed ad libitum for 24 hours period alternating with either complete or partial (modified) calorie restriction for the next 24 hours. MACR, the dietary strategy employed in the investigator's study, restricts 70% of an individual's daily requirement of calorie per day. There are other forms of intermittent fasting, for example, 2-4 days of ad libitum feeding alternating with 2-4 days of calorie restriction.
Currently, there are no approved pharmacological therapies for NAFLD, and many guidelines advocate recommendation with a focus on controlling risk factors and lifestyle interventions that include dietary and physical activities. No specific NAFLD trials have evaluated the effectiveness of modified form of intermittent fasting in the control of NAFLD activity.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Calorie restriction (MACR) | Experimental | Participants restricted 70% of their energy needs over 24 hours on a calorie restriction day alternate with a feeding day for the next 24 hours, where they were allowed eating (ad libitum). The calorie restriction and feeding days begun at 9 am each day, and on the calorie restriction day, meals were consumed between 2 pm and 8 pm to ensure that they underwent the same duration of calorie restriction. On each calorie restriction day, they were allowed energy-free beverages and sugar-free gum and encouraged to drink plenty of water. Diet plans were self-selected using detailed individualized food portion lists, meal plans, and recipes. Participants received phone calls from the investigator and four 2-weekly appointments with a dietitian. Adverse experiences were assessed every 2 weeks. |
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| Control group | No Intervention | Participants in the control group continued their usual habitual diet for 8 weeks. No specific dietary advice or educations were provided throughout the entire trial. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Calorie restriction (MACR) | Behavioral | This was a randomized, single-blind controlled trial with modified alternate-day calorie restriction (MACR) as the active intervention and normal habitual diet as control at Hospital University of Sains Malaysia. |
| Measure | Description | Time Frame |
|---|---|---|
| Change from baseline shear wave elastography (SWE) at 8 weeks | Through the intercostal approach, SWE measurements were performed in the right liver lobe, at the supine position with the right arm in maximal abduction. The sonographer, assisted by an ultrasonic time-motion image, located a liver portion of at least 6 cm thick, free of large vascular structures. Once the measurement area had been located, the sonographer pressed the probe button to start an acquisition. Patients were asked to hold their breath for about five seconds, while the stiffness of the region of interest was measured and 10 measurements were made for each patient and the median average value of those measurements was recorded in kilopascals (kPa: metric). | Change from baseline at 8-week |
| Change from baseline liver steatosis at 8 weeks | Ultra-sonographic measurements including liver steatosis and shear wave elastography (SWE) were performed with the SuperSonic Imagine's Aixplorer® Ultrasound machine (Super Sonic Image, Aix-en Provence, France). All measurements were performed by a single sonographer where the inter-observer agreement level with another experienced sonographer was 85%. | Change from baseline at 8-week |
| Concentration of high-density lipoprotein (HDL) | Blood samples (8-10 hours of fasting blood samples) were collected from participants at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L. | Change from baseline at 8-week |
| Concentration of low-density lipoprotein (LDL) | Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L. | Change from baseline at 8-week |
| Concentration of triglycerides (TG) |
| Measure | Description | Time Frame |
|---|---|---|
| Dietary plan adherence | Adherence data were assessed each week as percentage of adherence | At 8-week |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Yeong Yeh Lee, MD, PhD | Universiti Sains Malaysia | Principal Investigator |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 10, 2015 | Dec 29, 2018 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Oct 10, 2015 | Dec 29, 2018 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D065626 | Non-alcoholic Fatty Liver Disease |
| ID | Term |
|---|---|
| D005234 | Fatty Liver |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
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Participants who fulfilled the selection criteria were randomly assigned to the modified alternate-day calorie restriction (MACR) group or the control group after a 2 week run-in period. During the 2 weeks, participants were required to keep their body weight stable by maintaining their usual eating habits and their daily activities. Randomization was performed using a random number generator with recruitment aimed for three MACR participants for every control participant by principal investigator.
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Participants were blinded after assignment to interventions or control group.
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Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L.
| Change from baseline at 8-week |
| Concentration of total cholesterol (TC) | Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L. | Change from baseline at 8-week |
| Concentration of fasting blood sugar (FBS) | Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L. | Change from baseline at 8-week |
| Concentration of alanine aminotransferase (ALT) | Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in U/L. | Change from baseline at 8-week |
| Concentration of aspartate aminotransferase (AST) | Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in U/L. | Change from baseline at 8-week |