Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly termed Non-Alcoholic Fatty Liver Disease (NAFLD), has emerged as the dominant cause of chronic liver disease globally [1]. Affecting an estimated one-third of the adult population, MASLD encompasses a progressive spectrum from benign hepatic steatosis to steatohepatitis, fibrosis, and cirrhosis [2,3]. MASLD increasingly affects individuals with metabolic dysfunction, including those with End-Stage Kidney Disease (ESKD), where factors such as uremia, chronic inflammation, and insulin resistance contribute to liver fat deposition. Diagnosis in dialysis patients is often missed due to subtle clinical signs and limited imaging options. Transient Elastography (TE) provides a non-invasive method to detect MASLD early but remains underutilized in nephrology [4]. The American Association for the Study of Liver Diseases (AASLD) emphasizes lifestyle improvements, like healthy eating and regular exercise, as the primary treatment for fatty liver diseases. Losing weight through these changes can help reduce fat and inflammation in the liver. For those who do not have diabetes but have confirmed liver inflammation via biopsy, vitamin E may offer additional benefits by protecting liver cells [5]. In a few other recent studies, tocotrienol, a vitamin E isomer with potent antioxidant properties, has resulted in promising improvement in MASLD patients with type 2 DM as well [6], but has yet to be studied in kidney disease patients. This study employed the transient elastography technique for evaluating the prevalence of MASLD in ESKD patients. This is also the first study evaluating tocotrienol as a novel therapeutic agent for the treatment of MASLD in ESKD patients on dialysis.

Study Design and Setting

This prospective interventional study was conducted at two dialysis centers, TamilNad Kidney Research (TANKER) Foundation and MGM Hospitals Dialysis Centres in Chennai, India, between January and April 2024. The study was approved by the institutional ethics committee, and all participants provided informed consent. The design conformed to the ethical standards of the Declaration of Helsinki and followed CONSORT guidelines for interventional research.

Participant Selection

A total of 140 adult patients with ESKD undergoing maintenance hemodialysis were recruited through consecutive sampling. Inclusion criteria were age ≥ 18 years, on hemodialysis for at least three months, and willingness to undergo hepatic evaluation [1-3]. Exclusion criteria included known chronic liver disease unrelated to MASLD (e.g., hepatitis B or C, autoimmune hepatitis), history of significant alcohol use (>20 g/day for women, >30 g/day for men), normal renal function, and recent use of hepatotoxic or antioxidant medications [1-4].

Baseline Assessment and Diagnostics

All participants underwent non-invasive liver evaluation using transient elastography (TE) with the Fibrotouch FT100-HISKY device. Two parameters were collected:

• Ultrasound attenuation parameter (UAP), to quantify hepatic fat
• Liver stiffness measurement (LSM): to assess fibrosis

MASLD was classified based on UAP thresholds:

• Mild steatosis: UAP < 238 dB/m
• Moderate: 238–268 dB/m
• Severe: >268 dB/m
• Fibrosis staging was defined as:
• F0–F1: <7.0 kPa
• F2: 7.0–9.5 kPa
• F3: 9.6–12.5 kPa
• F4 (cirrhosis): >12.5 kPa

Comprehensive biochemical profiling was also performed, including alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), liver size, hemoglobin, platelet count, and serum creatinine. Lifestyle and clinical risk factors such as diabetes, hypertension, hepatitis status, and dialysis frequency were recorded through structured interviews and medical chart reviews.

Intervention Protocol

Participants with UAP > 250 dB/m (n = 39)—indicative of moderate-to-severe MASLD—were enrolled into the intervention arm. These individuals received Tocotrienol 200 mg softgel capsules (Tocofil TM, Fourrts India Laboratories), administered twice daily for a duration of three months. Adherence was monitored via pill count and dialysis nurse logs. No changes were made to the patients' routine dialysis regimen, dietary plans, or concurrent medications during the study period. No adverse events related to the intervention were reported.

Primary outcomes included:

• Change in UAP (hepatic steatosis)
• Change in ALT/SGPT (liver enzyme activity)
• Change in LSM (fibrosis)

Secondary outcomes included regression in steatosis grade and shifts in fibrosis staging distribution.

Statistical Analysis

Data were analyzed using SPSS version 26.0. Descriptive statistics summarized demographic and clinical characteristics. Paired t-tests assessed within-group changes pre- and post-intervention. Between-group comparisons were evaluated using independent t-tests and chi-square tests as appropriate. A multivariate linear regression model was constructed to adjust for potential confounders, including age, sex, BMI, diabetes status, and dialysis frequency. Statistical significance was set at p < 0.05.

Patient Characteristics

Tanker Cohort (n=120)

The cohort (N=120, mean age ± SD 49.4 ± 12.6) was primarily male (73.3%), with most undergoing twice-weekly dialysis (70%). Average BMI ± SD was 21 ± 13.0. Lifestyle risk factors were low: smoking (4.2%), alcohol use (11.7%), and nearly all consumed a non-vegetarian diet (99.2%). 24-hour dietary recall was done for all patients. The average liver size was 12.27 cm (range of 9.86–14.9 cm) (Table 1). Risk factors including diabetes, hypertension, obesity, hepatitis B & hepatitis C were evaluated (Table 2, Figure 1).

Table 1: Analysis of Participant Demographics, Clinical Data, and Liver Size (N = 120).

Table 2: Risk Factor Prevalence (N = 120).

Figure 1: Risk Factor Prevalence (N = 120).

Bar chart summarizing systemic comorbidities, highlighting hypertension (88.3%) and diabetes (31.7%) as the dominant cardiometabolic risk factors.

MGM Cohort (n = 20)

The demographic and lifestyle profile of this cohort (N=20) is summarized in Table 3. The subgroup (mean age 60.2 ± 19) was older and had a balanced sex ratio. Most received twice-weekly dialysis (60%), with a mean BMI of 23.5. Smoking and alcohol use were 15% (n=3) and 25% (n=5), and 90% followed a non-vegetarian diet. Liver size average 13.01 cm (range 10.6-16.5 cm). All completed a 24-hour dietary recall (Table 3).

Table 3: Analysis of Participant Demographics, Clinical Data, and Liver Size (N = 20).

Prevalence of MASLD in ESKD

Among the 120 ESKD patients studied, 35.8% (77 patients) exhibited hepatic steatosis based on UAP scores exceeding 238 dB/m. Additionally, 47.5% (57 patients) had liver stiffness values above 7 kPa, indicative of moderate to severe fibrosis (Figure 2). When liver enzyme elevations were also considered (ALT > 40 U/L), nearly 71.7% of patients demonstrated some form of occult liver pathology. At MGM Hospitals dialysis center no patient had a UAP score higher than 238 dB/m; however, 10 out of 20 patients, that is, 50% of patients, had liver stiffness >7 kPa, likely indicating more advanced liver disease in this cohort due to the older age. In addition, 5% of the patients had elevated transaminases.

Figure 2: Histogram of Hepatic Steatosis by UAP Score (N = 120).

Figure 2: Histogram depicting hepatic steatosis burden stratified by UAP thresholds, indicating that the majority of patients (64.2%) fell below the diagnostic cutoff, while 35.8% exhibited moderate to severe steatosis. 47.5% (without/o of hep B & C) had liver stiffness >7kPa indicating advanced liver disease in ESKD patients.

Combining both centers (n=140), 47.8% of patients had liver stiffness >7 kPa, and 30% of the patients had UAP scores higher than 238 dB/m. This highlights a significantly elevated prevalence of liver disease in ESKD patients compared to the general population, underlining the need for routine liver screening in dialysis centers.

Post-Intervention Findings

Baseline Liver Enzyme and Fibrosis Profiles in the Tocotrienol Group at Tanker Foundation

39 patients with UAP > 250 dB/m were enrolled into the tocotrienol interventional arm. Baseline data revealed a mean ALT of 52.6 U/L and liver stiffness of 7.9 kPa, indicating mild to moderate fibrosis in some cases. Fibrosis staging showed 56.4% (n = 22) with F0–F1 (no/minimal fibrosis), 28.2% (n = 11) with F2 (moderate), 10.3% (n = 4) with F3 (advanced), and 5.1% (n = 2) with F4 (cirrhosis-range) as summarized in Table 4. This distribution indicates a notable subset of patients at risk for progressive liver disease and the need for timely intervention.

Table 4: Baseline Fibrosis Distribution in Tocotrienol Group (n = 39).

LSM = Liver Stiffness Measurement. Fibrosis stages were determined by transient elastography prior to tocotrienol intervention.

Impact of Tocotrienol on MAFLD Parameters

The 39 NAFLD patients were reassessed after three months of tocotrienol (200 mg twice daily) using biochemical tests and elastography to evaluate changes in steatosis, liver enzymes, and stiffness.

Change in Hepatic Steatosis: UAP Score

Hepatic steatosis showed notable improvement as per Figure 3.

• Baseline mean UAP: 267.2 dB/m
• Post-treatment mean UAP: 239.3 dB/m
• Mean change: -27.96 dB/m
• Statistical significance: p < 0.001,

This substantial decline of nearly 28 dB/m suggests tocotrienol effectively decreased liver fat, possibly through antioxidant or lipid-clearing mechanisms.

Figure 3: Pre- and Post-Treatment UAP Scores (n = 39).

This bar chart compares baseline (267.2 dB/m, blue) and post-treatment (239.3 dB/m, orange) UAP scores, highlighting a significant reduction in steatosis (p < 0.001).

Change in Liver Enzymes: ALT (SGPT)

Liver enzyme levels improved as per Figure 4:

• Baseline mean (ALT): 52.6 U/L
• Post-treatment mean (ALT): 42.9 U/L
• Mean change: -9.69 U/L
• Statistical significance: p = 0.045

This moderate but statistically significant reduction in ALT supports the hypothesis that tocotrienol exerts hepatoprotective effects, possibly through antioxidant and anti-inflammatory pathways.

Figure 4: Pre- and Post-Treatment SGPT (ALT) Trend (n = 39).

This line chart tracks the decline from baseline (52.6 U/L, blue) to post-treatment (42.9 U/L, green) SGPT values, showing a significant improvement (p = 0.045).

Change in Liver Stiffness

Liver stiffness changes were modest as per Figure 5:

• Baseline mean stiffness: 7.9 kPa
• Post-treatment mean stiffness: 6.3 kPa
• Mean change: -1.65 kPa
• Statistical significance: p = 0.063

Although not reaching statistical significance, the downward trend in fibrosis markers is clinically encouraging and warrants longer-term follow-up studies. It is possible that fibrosis regression, if achievable, requires extended durations of therapy or adjunctive interventions such as weight management and glycemic control.

Figure 5: Pre- and Post-Treatment Liver Stiffness (n = 39).

This line chart displays baseline (median 7.9 kPa, blue) and post-treatment (median 6.3 kPa, green) liver stiffness, reflecting a non-significant but promising trend (p = 0.063).

Multivariate Regression Analysis

A multivariate regression model was constructed to account for confounding variables such as age, sex, diabetes status, dialysis frequency, and BMI. Tocotrienol remained an independent predictor of improvement in UAP (β = −26.42, p < 0.01) and ALT (β = −8.88, p = 0.048), after adjusting for these covariates. These results strengthen the validity of the therapeutic signal observed and suggest a specific role for tocotrienol, rather than a coincidental improvement (Table 5).

Table 5: Multivariate Regression Results for Tocotrienol Effects (n = 39).

Observed Indicators of Therapeutic Potential

In the 39 NAFLD patients, the 3-month intervention resulted in:

• A 27.96 dB/m reduction in UAP (p < 0.001), indicating decreased liver fat.
• A 9.69 U/L reduction in SGPT (ALT) (p = 0.045), reflecting improved liver function.
• A non-significant 1.65 kPa reduction in liver stiffness (p = 0.063), suggesting potential benefits with extended therapy.

These effects, validated by regression analysis, were independent of confounders such as age, sex, diabetes status, and BMI, suggesting a direct therapeutic impact.

This study offers important new insights into the burden and potential management of MASLD in patients with end-stage renal disease (ESKD) undergoing maintenance hemodialysis. Using non-invasive hepatic imaging, we found higher evidence of occult liver disease, despite being predominantly non-obese and minimally exposed to classical hepatic risk factors. A targeted lifestyle and nutritional intervention over a three-month period was associated with statistically and clinically meaningful improvements in hepatic steatosis and transaminase levels, though changes in liver stiffness did not reach statistical significance.

The prevalence of MASLD in this ESKD cohort aligns with prior reports of hepatic fat accumulation in patients with chronic kidney disease, particularly those on dialysis. Notably, our findings parallel those of Lai et al. [7,8,11], who demonstrated a MASLD prevalence of 30–40% in CKD patients using elastography-based methods. However, this study is among the first to apply these methods to an Indian ESKD population, where routine hepatic screening remains uncommon. The high rate of subclinical steatosis—identified in patients with average BMI values and no alcohol use—underscores the unique pathophysiological environment of uremia, which may facilitate liver fat accumulation independent of traditional metabolic risk. Mechanistically, MASLD in ESKD may be driven by uremia-induced oxidative stress, gut-derived endotoxemia, insulin resistance, and mitochondrial dysfunction, which likely contribute to steatosis and mild fibrosis seen in elastography. Silent progression, with normal or mildly elevated liver enzymes, supports the need for routine noninvasive liver monitoring in renal care [2]. The therapeutic component of this study is also noteworthy. Tocotrienol, a lesser-known isomer of vitamin E, demonstrated a significant reduction in both UAP scores and ALT levels. These findings are consistent with animal studies showing tocotrienol’s capacity to inhibit hepatic lipogenesis, reduce inflammatory cytokines, and enhance mitochondrial β-oxidation [2,9]. While prior human studies have focused primarily on α-tocopherol, our results suggest that tocotrienol may offer superior hepatoprotective effects, particularly in populations with limited therapeutic options. Importantly, the absence of adverse events during the trial also highlights tocotrienol’s potential safety in ESKD, where pharmacologic fragility is a major concern. The good safety profile supports its potential as a hepatoprotective agent in ESKD patients with limited treatment options.

Future directions should include larger, randomized controlled trials with extended follow-up, metabolic and fibrosis biomarkers, and combined lifestyle-pharmacological approaches to optimize liver and renal outcomes.

The global prevalence of MASLD is estimated to be approximately 32%, with nearly one in three individuals affected. Among patients with end-stage kidney disease (ESKD) undergoing dialysis, the prevalence is notably higher, and these individuals frequently exhibit more advanced hepatic involvement, as indicated by elevated liver stiffness scores. Transient elastography represents a non-invasive and reliable modality for the assessment and longitudinal monitoring of liver health in this population. The present study underscores the necessity of routine hepatic surveillance in patients receiving dialysis. Moreover, tocotrienol supplementation was associated with significant reductions in hepatic steatosis and improvements in liver enzyme profiles, suggesting potential therapeutic benefit in this high-risk cohort. Nevertheless, larger, well-designed randomized controlled trials are required to validate these findings and establish clinical efficacy.

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