VLCD efficacy in the treatment of NAFLD.

Study design: The investigators plan to perform a controlled, non-randomized, open-label, pilot clinical trial to evaluate the effect of an 8-week VLCD intervention on NAFLD. The main variable of this study is the magnitude of liver steatosis and fibrosis assessed non-invasively by elastography. The investigators will compare these variables before and after the VLCD intervention. Hereby, it is hypothesized that VLCD reduces liver steatosis and fibrosis.

Study Subjects: Potential adult participants with obesity \[age ≥ 18 years old; body mass index (BMI) ≥ 30 kg/m2 and ≤ 50 kg/m2\] will be recruited at the Weight Management Clinic, at the Diabetes Center and at the Digestive Health Center, all at University of Iowa Health Care (UIHC). The investigators will invite potential participants with negative tests for viral hepatitis C and autoimmune hepatitis, and elastography results positive for fibrosis grade F0 through F4 and/or steatosis grade S1 through S3 within the last 6 months. The above tests, along with complete blood count (CBC), basic metabolic profile (BMP), thyroid stimulating hormone (TSH) with reflex free thyroxine (free T4) and hemoglobin A1c are routinely obtained as part of the standard of care at the recruitment clinics. Oral health status of these patients will be obtained from the available dental charts, if not, a dental examination will be performed. With Institutional Board Review (IRB) authorization, the investigators will interrogate the charts to verify whether subjects meet criteria for participation. Case managers will contact potential participants by telephone, electronic mail or letter.

Detailed sessions:

Week 0 Visit (enrolment visit): Subjects who meet the above criteria will be invited for week 0 visit at UIHC Preventive Intervention Center. Subjects will fast for 12 hours for week 0 visit. After signing informed consent, the inclusion/exclusion criteria will be reviewed again. Clinical history and physical exam will be charted from the last clinical note. Subjects will fill the AUDIT C, a screening questionnaire for alcohol consumption. Vitals signs (that is, seated and standing blood pressure and heart rate, ambient air pulse saturation of O2, weight, height, and neck and waist circumferences). Blood samples for sodium, potassium, creatinine, CBC, AST, ALT, triglycerides, glucose, insulin, A1c (table 1), miR, and platelets will also be drawn during week 0 visit. Female participants at reproductive age will be asked to provide urine sample for pregnancy test. Unstimulated saliva will be collected from the participants by asking them to spit into a collection tube. Supplies for stool collection with instructions for sample return will be provided for assessment of baseline fecal microbiome testing. Stools samples should be returned to the research center before VLCD initiation. The participant will also meet the research manager for education about the VLCD and lower calorie diet during week 0 visit. The research manager will dispense 2-week worth of Optifast® replacement meals.

Week 2 Visit: At the end of week 2, the participant who consumes VLCD, but not a lower calorie diet, will return to the UIHC Preventive Intervention Center, when vital signs will be assessed and blood samples for laboratory tests will be drawn (table 1). On week 2 visit, sodium, potassium and creatinine will be assessed. Participants will complete of an adverse event questionnaire. Very low-calorie diets will be dispensed at week 2 visit.

Week 4 Visit: At the end of week 4, the participant who consumes VLCD, but not a lower calorie diet, will return to the UIHC Preventive Intervention Center, when vital signs will be assessed and blood samples for laboratory tests will be drawn (table 1). On week 4 visit, sodium, potassium, creatinine, ALT, AST, and uric acid will be assessed. Participants will complete of an adverse event questionnaire. Very low-calorie diets will be dispensed at week 4 visit.

Week 8 Visit (closing visit): At the end of week 8, the participant who consumes VLCD or a lower calorie diet will return to the UIHC Preventive Intervention Center for week 8 visit. Subjects will fast 12 hours for week 8 visit when saliva and blood samples for sodium, potassium, creatinine, CBC, ALT, AST, triglycerides, glucose, insulin, A1c (table 1) and miR will be collected. The participant will be instructed to bring a stool sample for microbiome analysis using collection supplies dispensed beforehand. The post-VLCD elastography will be performed during the final visit. Participants will complete of an adverse event questionnaire. The participant will also meet the research manager and receive education about transitioning from VLCD to a low calorie, low fat diet during the closure visit. The participants will be recommended to weight themselves weekly after the VLCD intervention. The research manager will contact the participant by telephone or video-call to assess adherence to low calorie, low fat diet and to review the weight trajectory 1 month after termination of the study.

Telephone and/or video-call contacts: Between week 0 and 8 visits, the research manager will contact the participant by telephone or video-call on a weekly basis for diet compliance, and assessment of adherence, response and adverse events of VLCD or lower calorie diet for 8 weeks, and then for 4 weeks after termination of the diet. Therefore, the total time of participation in the study is 12 weeks.

Very low-calorie diet treatment: The VLCD program will last 8 weeks and then will be followed by a gradual re-introduction of food through the next 1 month. The only sources of nutrition during this phase are the Optifast® products providing up to 800 kcal per day. Two liters (67.63 fl oz) of water should also be consumed each day. Participants will receive Optifast® replacement meals at no cost. The replacement meals will be dispensed at the UIHC Preventive Intervention Center on weeks 0, 2, and 4. Participants will be instructed to use 5 replacement meals per day (800 kcal total) with 40% of calories as protein, 40% as carbohydrate, and 20% as fat (Ard, Lewis et al. 2019).