Impact of Lifestyle Interventions on Cognitive Decline in Non-alcoholic Fatty Liver Disease

Impact of Lifestyle Interventions on Cognitive Decline in NAFLD: A Randomized Controlled Trial of Liver Fibrosis, Hormonal Imbalance, and Inflammatory Markers

This study investigates whether a structured lifestyle program can help improve thinking skills and liver health in adults with Non-Alcoholic Fatty Liver Disease (NAFLD). We are enrolling 45 participants, aged 18-42, who will be randomly assigned to one of three groups for six months: one receiving general health advice, a second following a supervised Mediterranean diet plan, and a third combining the same diet with a regular walking program. The main goal is to see if these diet and exercise interventions can lead to better scores on memory and reasoning tests, reduce liver stiffness measured by a painless scan (FibroScan), and improve related blood markers of inflammation and hormone balance.

Study Overview

• Status: Recruiting
• Conditions: Neurocognitive Disorders; Non-Alcoholic Fatty Liver Disease
• Intervention / Treatment: Behavioral: Structured Mediterranean Diet; Behavioral: Control / General Advice

Detailed Description

This is a parallel-group, randomized controlled trial designed to evaluate the impact of lifestyle interventions on cognitive function in patients with NAFLD, and to explore associations with liver fibrosis severity and underlying biomarkers. The study aims to recruit 45 participants with imaging-confirmed NAFLD, who will be randomized (1:1:1) into a control group (general advice), a dietary intervention group (structured Mediterranean diet), or a combined intervention group (diet plus supervised exercise). Primary outcomes include cognitive performance measured by the Montreal Cognitive Assessment (MoCA) and serum T-Tau levels, assessed at baseline and after the 6-month intervention. Key secondary outcomes encompass changes in liver fibrosis (via FibroScan and FIB-4 index), inflammatory biomarkers (IL-6, TNF-α), and hormonal profiles (cortisol, testosterone, estradiol). The protocol has received ethical approval from the Khyber Medical University Institutional Review Board, and analysis will follow intention-to-treat principles using repeated-measures ANOVA and regression models to determine intervention efficacy and pathophysiological correlations.

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dr Ayesha Qaiser, MBBS, PhD Scholar; Phone Number: +92 332 9135697; Email: dr.ayeshaqaiser@hotmail.com
• Study Contact Backup: Name: Dr Inayat Shah, PhD; Phone Number: +92 332 1431414; Email: inayat.shah@kmu.edu.pk

Study Locations

• Pakistan
  • KPK
    • Peshawar, KPK, Pakistan, 25100
      • Recruiting
      • Khyber Teaching Hospital
      • Contact: Dr Ayesha Qaiser, PhD Scholar; Email: dr.ayeshaqaiser@hotmail.com
      • Contact: Dr Arshad Hussain, PhD; Phone Number: 03312710692; Email: Hussainadr@gmail.com
    • Peshawar, KPK, Pakistan, 25100
      • Recruiting
      • Northwest General Hospital
      • Contact: Dr Inayat Shah, PhD; Phone Number: +92 332 1431414; Email: inayat.shah@kmu.edu.pk
      • Contact: Dr Ayesha Qaiser, PhD Scholar; Phone Number: +92 332 9135697; Email: dr.ayeshaqaiser@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 to 42 years.
• Diagnosed with fatty liver (NAFLD) via imaging (e.g., ultrasound).
• Liver fibrosis assessed and staged via FibroScan and the FIB-4 index.
• Literate (to consent and complete cognitive assessments/questionnaires).

Exclusion Criteria:

• History of alcohol intake >20g/day.
• Chronic viral hepatitis B or C.
• Major neuropsychiatric illnesses.
• Pregnancy or breastfeeding.
• Chronic illnesses including Diabetes Mellitus and thyroid dysfunction.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mediterranean Diet Intervention; Participants will follow a structured, culturally adapted Mediterranean diet plan for 6 months, designed and supervised by a qualified dietitian. The diet emphasizes whole grains, vegetables, fruits, legumes, nuts, olive oil, and lean proteins (detailed 7-day plan in Annexure 7). Support includes individualized counseling, provision of meal plans, weekly food diaries, 24-hour dietary recalls, and monthly check-ins. Outcome assessments occur at T0, T1 (6 months), and T2 (12 months).	Behavioral: Structured Mediterranean Diet; A culturally adapted, structured dietary plan based on the Mediterranean diet principles, delivered through individual dietitian counseling, provision of weekly meal plans, and ongoing compliance support (food diaries, recalls, monthly check-ins).
Active Comparator: Control / General Advice; Participants will receive general verbal and written advice on healthy eating and physical activity, consistent with standard care. No structured diet plan or supervised exercise will be provided. They will undergo all outcome assessments (FibroScan, FIB-4, MoCA, biomarker blood draws) at Baseline (T0), 6 months (T1), and 12 months (T2).	Behavioral: Control / General Advice; This intervention consists of providing standardized, non-structured verbal and written information on the principles of a balanced diet and the benefits of regular physical activity, as per routine clinical practice. It serves as the active comparator representing minimal intervention.
Experimental: Combined Diet and Exercise Intervention; Participants will receive the identical Mediterranean diet intervention as Arm 2 plus a structured, progressive aerobic exercise program. The exercise consists of a 60-minute walking session, 5 days per week, for 6 months, progressing through conditioning, strength-building, and endurance phases (detailed in Annexure III). Compliance is monitored via exercise logs, fortnightly contact, and monthly check-ins. Outcome assessments occur at T0, T1 (6 months), and T2 (12 months).	Behavioral: Structured Mediterranean Diet; A culturally adapted, structured dietary plan based on the Mediterranean diet principles, delivered through individual dietitian counseling, provision of weekly meal plans, and ongoing compliance support (food diaries, recalls, monthly check-ins).; Behavioral: Control / General Advice; This intervention consists of providing standardized, non-structured verbal and written information on the principles of a balanced diet and the benefits of regular physical activity, as per routine clinical practice. It serves as the active comparator representing minimal intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of Heart Failure Hospitalization or Cardiovascular Death	Time to first adjudicated event of either hospitalization for worsening heart failure or cardiovascular death. Events will be confirmed by a blinded Clinical Events Committee (CEC).	From randomization up to study completion (maximum follow-up of 30 months).
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score	The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item, self-administered disease-specific questionnaire. The Overall Summary Score (OSS) aggregates the physical limitation, symptom frequency, quality of life, and social limitation domains. Scores range from 0 to 100, where higher scores indicate better health status. The outcome is the change in KCCQ-OSS from baseline.	Baseline, Month 12.
Change in N-terminal pro-brain natriuretic peptide (NT-proBNP)	The ratio of change in serum NT-proBNP level from baseline. NT-proBNP will be measured in pg/mL by a central laboratory using a standardized assay.	Baseline, Month 6.
All-cause Mortality	Time from randomization to death from any cause.	From randomization up to study completion (maximum follow-up of 30 months).

Collaborators and Investigators

• Sponsor: Khyber Medical University Peshawar
• Collaborators: Khyber Teaching Hospital; Northwest General Hospital and Research centre
• Investigators: Principal Investigator: Dr Ayesha Qaiser, PhD Scholar, Khyber Medical University Peshawar; Principal Investigator: Dr Inayat Shah, PhD, Institute of Basic Medical Sciences, Khyber Medical University; Principal Investigator: Dr Arshad Hussain, PhD, Northwest General Hospital, Peshawar

Publications and helpful links

General Publications

• Whitehead AL, Julious SA, Cooper CL, Campbell MJ. Estimating the sample size for a pilot randomised trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome variable. Stat Methods Med Res. 2016 Jun;25(3):1057-73. doi: 10.1177/0962280215588241. Epub 2015 Jun 19.
• Kjaergaard K, Mikkelsen ACD, Wernberg CW, Gronkjaer LL, Eriksen PL, Damholdt MF, Mookerjee RP, Vilstrup H, Lauridsen MM, Thomsen KL. Cognitive Dysfunction in Non-Alcoholic Fatty Liver Disease-Current Knowledge, Mechanisms and Perspectives. J Clin Med. 2021 Feb 9;10(4):673. doi: 10.3390/jcm10040673.
• Semmler G, Datz C, Reiberger T, Trauner M. Diet and exercise in NAFLD/NASH: Beyond the obvious. Liver Int. 2021 Oct;41(10):2249-2268. doi: 10.1111/liv.15024. Epub 2021 Aug 21.
• Ishiba H, Sumida Y, Tanaka S, Yoneda M, Hyogo H, Ono M, Fujii H, Eguchi Y, Suzuki Y, Yoneda M, Takahashi H, Nakahara T, Seko Y, Mori K, Kanemasa K, Shimada K, Imai S, Imajo K, Kawaguchi T, Nakajima A, Chayama K, Saibara T, Shima T, Fujimoto K, Okanoue T, Itoh Y; Japan Study Group of Non-Alcoholic Fatty Liver Disease (JSG-NAFLD). The novel cutoff points for the FIB4 index categorized by age increase the diagnostic accuracy in NAFLD: a multi-center study. J Gastroenterol. 2018 Nov;53(11):1216-1224. doi: 10.1007/s00535-018-1474-y. Epub 2018 May 9.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2025
• Primary Completion (Estimated): April 28, 2026
• Study Completion (Estimated): June 15, 2026

Study Registration Dates

• First Submitted: December 8, 2025
• First Submitted That Met QC Criteria: December 8, 2025
• First Posted (Actual): December 19, 2025

Study Record Updates

• Last Update Posted (Actual): December 19, 2025
• Last Update Submitted That Met QC Criteria: December 8, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Cognitive Decline; Liver Fibrosis; Non-Alcoholic Fatty Liver Disease; Hepatocerebral Syndrome; Metabolic dysfunction-Associated SteatoHepatitis
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Digestive System Diseases; Cognition Disorders; Liver Diseases; Fibrosis; Fatty Liver; Pathological Conditions, Signs and Symptoms; Cognitive Dysfunction; Non-alcoholic Fatty Liver Disease; Liver Cirrhosis; Neurocognitive Disorders
• Other Study ID Numbers: KMU/DIR/CTU/2025/010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data that underlie the results reported in the primary publication (including demographic, clinical, laboratory, and cognitive assessment data) will be made available to qualified researchers upon reasonable request. The data will be shared to achieve the aims in the approved proposal, subject to a data use agreement.
• IPD Sharing Time Frame: Data will become available 9 months after the publication of the primary results and will be accessible for 5 years.
• IPD Sharing Access Criteria: Data access requests should be directed to the corresponding author (Dr. Ayesha Qaiser) and will be reviewed by the trial's steering committee. Requestors will need to provide a methodologically sound proposal and sign a data use/access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No