Non-alcoholic Fatty Liver Disease, Non-alcoholic Steatohepatitis
Conditions
Keywords
High-intensity Interval Training
Brief summary
This pilot study aims to investigate whether 6 weeks of twice weekly High-intensity Interval Training (HIT) results in improvements in disease-specific measures, feelings of general well-being, physical fitness and cognitive function in patients with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.
Detailed description
The study aims to recruit up to 12 patients diagnosed with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) from the liver clinics at Ninewells Hospital, Dundee. Suitable patients who give informed consent will be assessed at baseline, again after 6 weeks of no intervention to act as a control period, and thirdly after 6 weeks of twice-weekly high-intensity interval training (HIT). Assessments will be performed with the patient fasted overnight, and will involve body composition measurements, blood pressure, a venous blood sample for circulating triglycerides, fasting glucose, insulin, liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and platelets. An oral glucose tolerance test will be performed using fingerprick capillary samples. Cognitive function tests for episodic memory, executive function and semantic memory will be performed and a questionnaire (SF-36) will be used to assess general well-being. Physical fitness will be assessed through a 12-minute walk test on a treadmill, which will allow estimation of maximal oxygen uptake capacity (VO2 max), and a get up and go test will be used to assess physical function. The exercise intervention will involve a 2 minute warm-up, cycling at 50 rpm before the participants will be asked to cycle at 100rpm and a weight will be added (7% body weight for men and 6% body weight for women) as resistance. The sprint will last 6 seconds and the participant will be asked to rest for at least 1 minute. This will be repeated for a total of 5 sprints in sessions 1-3, 6 sprints in session 4, 7 sprints in sessions 5&6, 8 sprints in sessions 7&8, 9 sprints in sessions 9&10 and 10 sprints in sessions 11&12. Exercise heart rate will be monitored and recorded. At least 3 days after the last HIT session the pre-intervention testing assessment will be repeated for a third time. Changes in measured variables will be analysed via repeated measures analysis of variance (ANOVA) with post-hoc testing of all variables.
Interventions
2 minute warm-up at 50rpm, then increase to 100rpm. Weight added to bike (7% body weight for men 6% body weight for women). Continue effort for 6 seconds, then passive rest for at least 1 minute. Total 5 sprints in sessions 1-3, 6 sprints in session4, 7 sprints in sessions 5&6, 8 sprints in sessions 7&8, 9 sprints in sessions 9&10 and 10 sprints in sessions 11&12.
Sponsors
Study design
Masking description
No Masking, this was not possible with this study design.
Eligibility
Inclusion criteria
* clinical diagnosis of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis * attending a specialist liver clinic at Ninewells Hospital, Dundee
Exclusion criteria
* unstable cardiovascular disease * uncontrolled arrhythmias * structural cardiac abnormalities * uncontrolled diabetes * other uncontrolled metabolic abnormalities * severe orthopaedic condition that would prohibit exercise * severe pulmonary condition that would prohibit exercise * any other poorly controlled medical condition. * resting systolic blood pressure above 160 mm Hg * resting diastolic blood pressure above 90 mm Hg * symptomatic postural drop in blood pressure greater than 20 mm Hg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | calculation of insulin resistance via formula: fasting insulin (mIU/L) x fasting glucose (mg/dL)/405 normal insulin resistance -HOMA score \<3 moderate insulin resistance -HOMA score 3-5 severe insulin resistance -HOMA score \>5 Assessed at baseline, after 6 week control period and within 1 week of completing 6 weeks HIT |
| Oral Glucose Tolerance Test | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | measurement of capillary samples for glucose at time 0, followed by every 20 minutes for 2 hours following ingestion of 75g glucose. Results graphed against time, then area under the curve calculated for each of the 3 assessments. |
| AST: ALT Ratio | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | ratio of liver enzymes aspartate aminotransferase (AST) to alanine aminotransferase (ALT). used as a diagnostic aid e.g. AST:ALT of more than 2:1 is characteristic of alcoholic liver disease whereas fatty steatosis and many other causes of liver disease, ratio is less than or equal to 1. Ratio may rise as fibrosis and cirrhosis develop in viral hepatitis. |
| FIB-4 | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | calculated from AST, ALT, platelets and participant's age and used to estimate amount of fibrosis in liver. Fib-4 score of \<1.45 has negative predictive value of 90% for advanced fibrosis. |
| Body Fat Mass Estimated Via Bioimpedance | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | total body fat and trunk fat estimated via bioimpedance measured after overnight fast, expressed as percentage |
| Blood Pressure | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | taken with participant supine, measured on left arm |
| General Well-being as Assessed by SF-36 Questionnaire | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | Assessment of: physical functioning, social functioning, mental health, pain, change in health, physical role limitation, mental role limitation, energy and vitality, health perception over preceding 4 weeks (other than change in health, which is a comparison to health the preceding year), expressed as a transformed score range 0-100, with a higher score indicating better function/freedom from pain etc |
| Short-term Memory Recall | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | testing of verbal word presentation-immediate recall of 10 words (60 seconds for recall) Maximum =10, minimum =0 |
| Estimated VO2 Max | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | VO2 max estimated via submaximal exercise test-submaximal treadmill walking test Calculated via formula: VO2max= 15.1+21.8 x speed (miles per hour) - 0.327 x heart rate (beats per minute) - 0.263 x speed x age (years) + 0.00504 x heart rate x age + 5.98 x gender (0=female, 1=male) |
| Physical Function-Get up and go Test | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | participant will be timed standing up from chair unaided,walking 30m, turning round and returning to a seated position on the chair, the average time of 3 attempts will be recorded. |
| Ankle Brachial Pressure Index (ABPI) | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | ratio of blood pressure in left arm and right ankle |
| Long-term Memory Recall | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | testing of verbal word presentation-delayed recall of 10 words 10 minutes after words initially presented (within 60 seconds). Maximum= 10 words, minimum = no words |
| Executive Function (Verbal Fluency Test) | Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks | written verbal fluency test: participant asked to write down as many English words as possible within 60 seconds, starting with a particular letter of the alphabet, excluding proper nouns or plurals. Baseline assessment-letter A Post Control assessment -letter S After HIT assessment -letter F |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High-intensity Interval Training (HIT) 6 week control period with no intervention then 6 weeks of twice weekly HIT
High-intensity Interval Training: 2 minute warm-up at 50rpm, then increase to 100rpm. Weight added to bike (7% body weight for men 6% body weight for women). Continue effort for 6 seconds, then passive rest for at least 1 minute. Total 5 sprints in sessions 1-3, 6 sprints in session4, 7 sprints in sessions 5&6, 8 sprints in sessions 7&8, 9 sprints in sessions 9&10 and 10 sprints in sessions 11&12. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | High-intensity Interval Training (HIT) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 45 years STANDARD_DEVIATION 8 |
| body mass index (BMI) | 29.6 kg/m^2 STANDARD_DEVIATION 3.8 |
| diagnosis Non-alcoholic Fatty Liver Disease (NAFLD) | 7 participants |
| diagnosis Non-alcoholic Steatohepatitis (NASH) | 5 participants |
| height | 1.71 metres STANDARD_DEVIATION 0.09 |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 12 |
| serious Total, serious adverse events | 1 / 12 |
Outcome results
Ankle Brachial Pressure Index (ABPI)
ratio of blood pressure in left arm and right ankle
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Assessment | Ankle Brachial Pressure Index (ABPI) | 1.15 ABPI | Standard Deviation 0.16 |
| After 6 Week Control Period | Ankle Brachial Pressure Index (ABPI) | 1.08 ABPI | Standard Deviation 0.18 |
| After HIT Assessment | Ankle Brachial Pressure Index (ABPI) | 1.13 ABPI | Standard Deviation 0.27 |
AST: ALT Ratio
ratio of liver enzymes aspartate aminotransferase (AST) to alanine aminotransferase (ALT). used as a diagnostic aid e.g. AST:ALT of more than 2:1 is characteristic of alcoholic liver disease whereas fatty steatosis and many other causes of liver disease, ratio is less than or equal to 1. Ratio may rise as fibrosis and cirrhosis develop in viral hepatitis.
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Assessment | AST: ALT Ratio | 0.5 ratio | Standard Deviation 0.2 |
| After 6 Week Control Period | AST: ALT Ratio | 0.5 ratio | Standard Deviation 0.2 |
| After HIT Assessment | AST: ALT Ratio | 0.5 ratio | Standard Deviation 0.2 |
Blood Pressure
taken with participant supine, measured on left arm
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baseline Assessment | Blood Pressure | diastolic blood pressure | 85 mmHg | Standard Deviation 13 |
| Baseline Assessment | Blood Pressure | systolic blood pressure | 139 mmHg | Standard Deviation 18 |
| After 6 Week Control Period | Blood Pressure | systolic blood pressure | 142 mmHg | Standard Deviation 13 |
| After 6 Week Control Period | Blood Pressure | diastolic blood pressure | 87 mmHg | Standard Deviation 10 |
| After HIT Assessment | Blood Pressure | systolic blood pressure | 136 mmHg | Standard Deviation 19 |
| After HIT Assessment | Blood Pressure | diastolic blood pressure | 78 mmHg | Standard Deviation 8 |
Body Fat Mass Estimated Via Bioimpedance
total body fat and trunk fat estimated via bioimpedance measured after overnight fast, expressed as percentage
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baseline Assessment | Body Fat Mass Estimated Via Bioimpedance | total fat | 29.7 percentage body fat | Standard Deviation 8.2 |
| Baseline Assessment | Body Fat Mass Estimated Via Bioimpedance | trunk fat | 26.6 percentage body fat | Standard Deviation 6 |
| After 6 Week Control Period | Body Fat Mass Estimated Via Bioimpedance | total fat | 29.5 percentage body fat | Standard Deviation 8.3 |
| After 6 Week Control Period | Body Fat Mass Estimated Via Bioimpedance | trunk fat | 29.1 percentage body fat | Standard Deviation 5.4 |
| After HIT Assessment | Body Fat Mass Estimated Via Bioimpedance | total fat | 28.3 percentage body fat | Standard Deviation 7.1 |
| After HIT Assessment | Body Fat Mass Estimated Via Bioimpedance | trunk fat | 28.6 percentage body fat | Standard Deviation 5.7 |
Estimated VO2 Max
VO2 max estimated via submaximal exercise test-submaximal treadmill walking test Calculated via formula: VO2max= 15.1+21.8 x speed (miles per hour) - 0.327 x heart rate (beats per minute) - 0.263 x speed x age (years) + 0.00504 x heart rate x age + 5.98 x gender (0=female, 1=male)
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Assessment | Estimated VO2 Max | 34.9 millilitres/kilogram/minute | Standard Deviation 6.5 |
| After 6 Week Control Period | Estimated VO2 Max | 37.6 millilitres/kilogram/minute | Standard Deviation 7.2 |
| After HIT Assessment | Estimated VO2 Max | 38.5 millilitres/kilogram/minute | Standard Deviation 7.2 |
Executive Function (Verbal Fluency Test)
written verbal fluency test: participant asked to write down as many English words as possible within 60 seconds, starting with a particular letter of the alphabet, excluding proper nouns or plurals. Baseline assessment-letter A Post Control assessment -letter S After HIT assessment -letter F
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Assessment | Executive Function (Verbal Fluency Test) | 8 words | Standard Deviation 4 |
| After 6 Week Control Period | Executive Function (Verbal Fluency Test) | 12 words | Standard Deviation 4 |
| After HIT Assessment | Executive Function (Verbal Fluency Test) | 11 words | Standard Deviation 3 |
FIB-4
calculated from AST, ALT, platelets and participant's age and used to estimate amount of fibrosis in liver. Fib-4 score of \<1.45 has negative predictive value of 90% for advanced fibrosis.
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Assessment | FIB-4 | 0.68 Fibrosis Score | Standard Deviation 0.18 |
| After 6 Week Control Period | FIB-4 | 0.60 Fibrosis Score | Standard Deviation 0.19 |
| After HIT Assessment | FIB-4 | 0.60 Fibrosis Score | Standard Deviation 0.18 |
General Well-being as Assessed by SF-36 Questionnaire
Assessment of: physical functioning, social functioning, mental health, pain, change in health, physical role limitation, mental role limitation, energy and vitality, health perception over preceding 4 weeks (other than change in health, which is a comparison to health the preceding year), expressed as a transformed score range 0-100, with a higher score indicating better function/freedom from pain etc
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baseline Assessment | General Well-being as Assessed by SF-36 Questionnaire | Pain | 78 units on a scale | Standard Deviation 13 |
| Baseline Assessment | General Well-being as Assessed by SF-36 Questionnaire | Health Perception | 58 units on a scale | Standard Deviation 19 |
| Baseline Assessment | General Well-being as Assessed by SF-36 Questionnaire | Physical Role Limitation | 79 units on a scale | Standard Deviation 27 |
| Baseline Assessment | General Well-being as Assessed by SF-36 Questionnaire | Change in Health | 50 units on a scale | Standard Deviation 18 |
| Baseline Assessment | General Well-being as Assessed by SF-36 Questionnaire | Physical Function | 79 units on a scale | Standard Deviation 25 |
| Baseline Assessment | General Well-being as Assessed by SF-36 Questionnaire | Energy/Vitality | 58 units on a scale | Standard Deviation 18 |
| Baseline Assessment | General Well-being as Assessed by SF-36 Questionnaire | Mental Health | 71 units on a scale | Standard Deviation 17 |
| Baseline Assessment | General Well-being as Assessed by SF-36 Questionnaire | Social Function | 78 units on a scale | Standard Deviation 31 |
| Baseline Assessment | General Well-being as Assessed by SF-36 Questionnaire | Mental Role Limitation | 76 units on a scale | Standard Deviation 24 |
| After 6 Week Control Period | General Well-being as Assessed by SF-36 Questionnaire | Change in Health | 53 units on a scale | Standard Deviation 15 |
| After 6 Week Control Period | General Well-being as Assessed by SF-36 Questionnaire | Physical Function | 85 units on a scale | Standard Deviation 22 |
| After 6 Week Control Period | General Well-being as Assessed by SF-36 Questionnaire | Social Function | 82 units on a scale | Standard Deviation 27 |
| After 6 Week Control Period | General Well-being as Assessed by SF-36 Questionnaire | Mental Health | 69 units on a scale | Standard Deviation 20 |
| After 6 Week Control Period | General Well-being as Assessed by SF-36 Questionnaire | Pain | 72 units on a scale | Standard Deviation 28 |
| After 6 Week Control Period | General Well-being as Assessed by SF-36 Questionnaire | Physical Role Limitation | 79 units on a scale | Standard Deviation 31 |
| After 6 Week Control Period | General Well-being as Assessed by SF-36 Questionnaire | Mental Role Limitation | 76 units on a scale | Standard Deviation 34 |
| After 6 Week Control Period | General Well-being as Assessed by SF-36 Questionnaire | Energy/Vitality | 56 units on a scale | Standard Deviation 20 |
| After 6 Week Control Period | General Well-being as Assessed by SF-36 Questionnaire | Health Perception | 60 units on a scale | Standard Deviation 17 |
| After HIT Assessment | General Well-being as Assessed by SF-36 Questionnaire | Mental Health | 77 units on a scale | Standard Deviation 20 |
| After HIT Assessment | General Well-being as Assessed by SF-36 Questionnaire | Physical Function | 92 units on a scale | Standard Deviation 16 |
| After HIT Assessment | General Well-being as Assessed by SF-36 Questionnaire | Mental Role Limitation | 81 units on a scale | Standard Deviation 30 |
| After HIT Assessment | General Well-being as Assessed by SF-36 Questionnaire | Social Function | 83 units on a scale | Standard Deviation 27 |
| After HIT Assessment | General Well-being as Assessed by SF-36 Questionnaire | Health Perception | 61 units on a scale | Standard Deviation 17 |
| After HIT Assessment | General Well-being as Assessed by SF-36 Questionnaire | Change in Health | 67 units on a scale | Standard Deviation 18 |
| After HIT Assessment | General Well-being as Assessed by SF-36 Questionnaire | Pain | 88 units on a scale | Standard Deviation 16 |
| After HIT Assessment | General Well-being as Assessed by SF-36 Questionnaire | Energy/Vitality | 64 units on a scale | Standard Deviation 21 |
| After HIT Assessment | General Well-being as Assessed by SF-36 Questionnaire | Physical Role Limitation | 90 units on a scale | Standard Deviation 22 |
Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)
calculation of insulin resistance via formula: fasting insulin (mIU/L) x fasting glucose (mg/dL)/405 normal insulin resistance -HOMA score \<3 moderate insulin resistance -HOMA score 3-5 severe insulin resistance -HOMA score \>5 Assessed at baseline, after 6 week control period and within 1 week of completing 6 weeks HIT
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Assessment | Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | 6.9 units on a scale | Standard Deviation 4.7 |
| After 6 Week Control Period | Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | 9.6 units on a scale | Standard Deviation 10.5 |
| After HIT Assessment | Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | 7.0 units on a scale | Standard Deviation 4.3 |
Long-term Memory Recall
testing of verbal word presentation-delayed recall of 10 words 10 minutes after words initially presented (within 60 seconds). Maximum= 10 words, minimum = no words
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Assessment | Long-term Memory Recall | 4 words | Standard Deviation 1 |
| After 6 Week Control Period | Long-term Memory Recall | 5 words | Standard Deviation 2 |
| After HIT Assessment | Long-term Memory Recall | 5 words | Standard Deviation 2 |
Oral Glucose Tolerance Test
measurement of capillary samples for glucose at time 0, followed by every 20 minutes for 2 hours following ingestion of 75g glucose. Results graphed against time, then area under the curve calculated for each of the 3 assessments.
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Assessment | Oral Glucose Tolerance Test | 981 mmol/L*min | Standard Deviation 136 |
| After 6 Week Control Period | Oral Glucose Tolerance Test | 1030 mmol/L*min | Standard Deviation 182 |
| After HIT Assessment | Oral Glucose Tolerance Test | 1010 mmol/L*min | Standard Deviation 247 |
Physical Function-Get up and go Test
participant will be timed standing up from chair unaided,walking 30m, turning round and returning to a seated position on the chair, the average time of 3 attempts will be recorded.
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Assessment | Physical Function-Get up and go Test | 6.61 seconds | Standard Deviation 0.77 |
| After 6 Week Control Period | Physical Function-Get up and go Test | 6.23 seconds | Standard Deviation 0.59 |
| After HIT Assessment | Physical Function-Get up and go Test | 5.87 seconds | Standard Deviation 0.63 |
Short-term Memory Recall
testing of verbal word presentation-immediate recall of 10 words (60 seconds for recall) Maximum =10, minimum =0
Time frame: Baseline, Follow up at 6 Weeks and following HIT intervention at 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline Assessment | Short-term Memory Recall | 6 words | Standard Deviation 2 |
| After 6 Week Control Period | Short-term Memory Recall | 7 words | Standard Deviation 1 |
| After HIT Assessment | Short-term Memory Recall | 6 words | Standard Deviation 2 |