Abstract
Background
Liver cirrhosis is a progressive disease that can lead to serious complications including malnutrition which worsen the patient’s condition and pose a significant threat to life. The choice of protein source plays a crucial role in the clinical management of these patients; however, concerns remain regarding their nutritional adequacy and patient tolerance.
Objective
This RCT evaluated the effects of a diet based on vegetable and dairy protein versus a standard isocaloric, isonitrogenous diet on nutritional status and liver disease severity in cirrhotic patients.
Methods
Forty-six adults with liver cirrhosis were randomized using a computer-generated random number sequence into two groups for a 12-week intervention. Malnutrition status based on the Royal Free Hospital-Global Assessment (RFH-GA), Model for End-Stage Liver Disease (MELD) score (as the primary outcome) as well as dietary intake, anthropometric measurements, and biochemical parameters, including serum albumin and total protein were assessed at baseline and at study completion. The intervention group received a diet where the primary protein sources were from vegetables (e.g., legumes, soy) and dairy (e.g., milk, yogurt, cheese). Both groups followed an isocaloric, isonitrogenous diet, ensuring total protein intake was adequate and comparable. Intake records and interviews monitored dietary adherence.
Results
Compared to controls, the intervention group showed significant improvements in MELD score (-1.87; 95% CI: -3.03 to -0.71, p-between < 0.01), serum creatinine (-0.04; 95% CI: -0.14 to -0.01, p-between = 0.01), and INR (-0.10; 95% CI: -0.17 to -0.02, p-between = 0.01). Although serum total protein decreased within the intervention group (-0.25 ± 0.11, p-within = 0.03), the between-group difference was not significant (-0.21; 95% CI: -0.49 to 0.06, p-between = 0.13), and there were no changes in serum albumin or nutritional status categories—suggesting no clinical deterioration.
Conclusions
Adherence to a 12-week vegetable- and dairy-based protein diet in patients with liver cirrhosis significantly reduced short-term disease severity without adversely affecting nutritional status. Longer-term studies are needed to evaluate the durability of these effects.
Trial registration
The trial was registered in the Iranian Registry of Clinical Trials on June 8, 2023, under the registration number IRCT20220426054667N2. The full trial record can be accessed at https://irct.behdasht.gov.ir/trial/69973.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s40795-026-01426-w.
Keywords: Liver cirrhosis, Vegetable and dairy protein, MELD score, Nutritional status, Liver disease severity
Introduction
Liver cirrhosis is a progressive liver disease characterized by the gradual destruction of liver architecture and accumulation of fibrosis, ultimately resulting in liver failure. This condition is associated with numerous severe complications including ascites, esophageal variceal bleeding, hepatic encephalopathy, and recurrent infections. The severity of cirrhosis, often marked by these complications, is a critical determinant of patient survival and quality of life [1–5].
The Model for End-Stage Liver Disease (MELD) score is a widely used tool to assess disease severity in cirrhotic patients, calculated using specific biochemical parameters including bilirubin, creatinine, and INR. A higher MELD score indicates more advanced disease and poorer prognosis, with an increased risk of mortality and need for liver transplantation. This score serves as a primary criterion for prioritizing patients on liver transplant waiting lists [6–9]. However, disease severity assessed solely by MELD does not fully capture the clinical complexity, as nutritional status acts as an independent prognostic factor.
Among complications of cirrhosis, malnutrition poses a major clinical challenge, directly impacting treatment outcomes, accelerating disease progression, and increasing mortality [10]. Nutritional biomarkers such as serum albumin and total protein are commonly used to assess nutritional status in these patients; however, their levels are influenced not only by dietary intake but also by hepatic synthetic capacity and fluid shifts [11–13]. Despite this limitation, reduced levels of these proteins are consistently associated with adverse outcomes, including compromised immune function, increased infections, and diminished quality of life [14, 15].
While the importance of protein source is recognized in the management of cirrhotic patients, the optimal source of dietary protein remains a subject of debate. Some studies have investigated diets based on vegetable proteins or similar dietary patterns; however, the evidence is limited and inconsistent [16–18]. Moreover, significant concerns remain among some experts regarding the nutritional status of these patients. Many specialists worry that such diets may exacerbate malnutrition for various reasons, including decreased appetite, gastrointestinal disturbances, and poor tolerance to high fiber content, potentially leading to inadequate nutrient intake. This issue is particularly important because malnutrition is associated with severe consequences, including muscle wasting, reduced treatment tolerance, and increased mortality in cirrhotic patients.
To our knowledge, no study has specifically isolated the effect of protein source from protein quantity. Existing trials have compared different types of diets without controlling for total caloric and nitrogen intake [19]. Consequently, it remains unclear whether substituting predominantly animal-based proteins with vegetable and dairy proteins, while keeping the total protein and energy intake strictly constant (isocaloric and isonitrogenous), confers therapeutic benefit or poses a risk of worsening nutritional status in cirrhotic patients.
Therefore, this randomized controlled trial was designed to assess the impact of a 12-week isocaloric and isonitrogenous dietary intervention, replacing animal protein with vegetable and dairy protein sources, compared to a standard diet containing mixed protein sources. The study evaluates effects on liver disease severity, as measured by the MELD score, alongside nutritional status in patients with liver cirrhosis, aiming to clarify the potential therapeutic benefits and feasibility of this dietary modification. We hypothesized that a 12-week dietary intervention based on vegetable- and dairy-based protein would improve the MELD score and related biochemical parameters in patients with liver cirrhosis, while maintaining stable nutritional status as measured by the RFH-GA and anthropometric indices.
Methods
This study was designed as a randomized controlled clinical trial to evaluate the effects of a vegetable and dairy protein-based diet compared to a standard isocaloric and isonitrogenous diet in patients with liver cirrhosis.
Ethical considerations
The Tehran University of Medical Sciences Ethics Committee approved this clinical trial (approval number IR.TUMS.MEDICINE.REC.1402.060), which was conducted in accordance with the Declaration of Helsinki. The trial is registered in the Iranian Registry of Clinical Trials (registration no. IRCT20220426054667N2) as of June 8, 2023. The study adhered to the CONSORT guidelines, and all participants provided written informed consent before enrollment.
Sample size calculation
The sample size in this study was calculated based on the MELD score using data from the Maharshi et al. study [19]. The effect size (Cohen’s d) calculated from the changes in the MELD score (ΔMELD) in that study was 0.8. Accordingly, using G*Power software (version 3.1), with a significance level of 0.05 (two-tailed) and 80% power for comparing two independent means, the required sample size was estimated to be 21 participants per group. This number was increased to 23 participants per group to account for an anticipated dropout rate of approximately 10%. This sample size provides adequate power for the primary outcome MELD but is insufficient to detect small to moderate effects in secondary outcomes. Therefore, null findings for nutritional outcomes should be interpreted with caution, as they may reflect insufficient power rather than absence of effect.
Study population
A total of 1,315 individuals were initially screened, and after applying the inclusion and exclusion criteria, 46 patients were recruited from gastroenterology clinics in Tehran between September 2023 and June 2024.
The inclusion criteria for the study were: diagnosis of liver cirrhosis by a physician for at least six months, age range between 30 and 60 years, and willingness to participate in the study. Individuals were excluded if they had any of the following: advanced liver disease (MELD score > 18 or Child–Pugh class C); active gastrointestinal bleeding; serum creatinine above 1.5 mg/dL in the past month; alcohol or tobacco use in the past six months; pregnancy or breastfeeding; or diagnosed comorbidities including diabetes, pulmonary disease, heart failure, psychiatric disorders, hepatocellular carcinoma or other cancers, acute viral hepatitis, cholestatic or autoimmune cirrhosis, other autoimmune diseases, hyperuricemia, or musculoskeletal diseases. Additionally, those using corticosteroids or immunosuppressive drugs were not included. The exclusion criteria were occurrence of serious complications requiring hospitalization, diagnosis of any new disease during the study period, liver transplantation, and non-adherence to the study protocol (less than 70% compliance).
Study design and randomization
All enrolled patients completed a one-week run-in period prior to randomization, during which baseline demographic and clinical data were collected to confirm eligibility and clinical stability. Subsequently, participants were matched into pairs according to age (30–45 vs. 46–60 years), sex, and malnutrition status (adequately nourished, moderately malnourished, or severely malnourished). Within each matched pair, subjects were randomly allocated 1:1 to either the intervention (n = 23) or control (n = 23) group using block randomization with a block size of 2. Random sequence generation was performed by an independent statistician not involved in participant recruitment or data collection using Random Allocation Software (RAS). Malnutrition status was determined by the Royal Free Hospital-Global Assessment (RFH-GA) algorithm [20]. Allocation concealment was not implemented, as group assignment was revealed directly after baseline assessments. Due to the nature of the dietary intervention, participants and the dietitian providing dietary counseling could not be blinded to group assignment. However, laboratory staff conducting biochemical analyses, outcome assessors performing anthropometric measurements, and the statistician performing data analysis were blinded to group allocation until after the primary analysis was completed.
Intervention
Individual energy requirements were calculated by the Harris-Benedict equation and multiplied by 1.3 to estimate total energy expenditure. Diet macronutrient composition was prescribed as 1.2 g/kg protein, 30% fat, and 50–55% carbohydrates. Required amounts from each food group were determined, and a meal plan consisting of three main meals and four snacks was provided. The intervention group received a diet in which all prescribed protein sources were exclusively from vegetables (legumes, soy products, grains, nuts) and dairy (milk, yogurt, cheese). The prescribed diet aimed for 100% of total daily protein intake from combined vegetable and dairy sources, with no animal protein included in the meal plans. Specifically, the prescribed distribution of protein sources in the intervention group was approximately 70–80% from vegetable sources and 20–30% from dairy sources, depending on individual patient preferences and tolerances, while maintaining the isonitrogenous prescription. However, recognizing that complete elimination of animal protein may be challenging for some patients in real-world settings, dietary adherence was defined as achieving ≥ 70% of total protein intake from vegetable and dairy sources. This pragmatic threshold allowed for occasional consumption of animal protein outside prescribed meals while maintaining a meaningful contrast between groups. The control group received a standard diet with protein from mixed sources, typically comprising 40–50% animal protein (meat, poultry, fish, eggs) and 50–60% vegetable and dairy proteins combined. Within the vegetable and dairy component of the control diet, the proportion was approximately 40–45% from vegetable sources and 10–15% from dairy sources. The diets were prescribed for 12 weeks in the form of a menu consisting of three meals and four snacks.
All participants received individualized meal plans based on their calculated energy and protein requirements, with standardized exchange lists and sample menus. Dietary counseling was provided at baseline and at weeks 3, 6, and 9 (3 sessions total) by a registered dietitian. Each session lasted 30–45 min and included review of food records, reinforcement of dietary principles, and problem-solving for adherence barriers.
To minimize contamination, control group participants were explicitly counseled to maintain their usual dietary patterns without intentionally increasing vegetable and dairy protein consumption beyond their habitual intake. The intervention group was specifically instructed on identifying and incorporating vegetable and dairy protein sources while avoiding animal protein. Separate group counseling sessions were conducted to prevent cross-contamination of dietary advice.
Study measurements
The primary outcome of this study was the change in MELD score from baseline to 12 weeks. Secondary outcomes included changes in RFH-GA categories, individual biochemical parameters (serum bilirubin, creatinine, INR, albumin, and total protein), and anthropometric measurements (weight, BMI, triceps skinfold thickness, mid-arm circumference, and mid-arm muscle circumference).
Prior to the intervention, all enrolled patients (n = 46) underwent a one-week run-in period during which baseline demographic and clinical information including age, sex, socioeconomic status, education level, medical history, medication and supplement use, as well as alcohol and tobacco consumption were collected using a comprehensive general questionnaire (see supplementary S1). Dietary intake was evaluated using three-day food records (including one weekend day) to estimate baseline nutrient and energy consumption (see supplementary S3). During the study, dietary intake was monitored longitudinally through food records collected on one day during weeks 3, 6, and 9, and another three-day food record (including a weekend day) at the end of the study. This longitudinal dietary monitoring allowed assessment of dietary adherence and intake patterns. All dietary data were converted to grams and analyzed for total energy, macronutrients, and fiber using Nutritionist IV software (First Databank, San Bruno, CA, USA) adapted for Iranian foods by incorporating the nutrient composition of commonly consumed Iranian dishes from the Iranian Food Composition Table (Ministry of Health, Tehran, Iran). For mixed dishes, standardized recipes were developed based on common preparation methods. Participants were trained to record detailed descriptions of foods, and all records were reviewed with participants within 48 h for completeness.
Diet adherence measurements
Dietary adherence was assessed using two complementary measures. First, dietary compliance in the intervention group, which emphasized vegetable- and dairy-based proteins, was assessed by calculating the percentage of total daily protein intake derived from these sources relative to the total daily protein intake:(grams of protein from vegetable and dairy sources/total daily protein intake) × 100. Additionally, caloric compliance in both groups was evaluated as the percentage of actual caloric intake relative to the prescribed caloric target. If energy intake exceeded 100% of prescription, the excess was subtracted from 100%. In both measures, a value below 70% was considered indicative of non-compliance. This threshold was chosen for two reasons: First, given that dietary adherence in patients with cirrhosis is often suboptimal [21], a realistic target was needed to accommodate real-world challenges while ensuring meaningful dietary modification. Second, complete elimination of animal protein (100% adherence) is often difficult for patients in outpatient settings, and the 70% cutoff ensures sufficient contrast between groups while allowing practical flexibility.
Anthropometric measurements
Anthropometric measurements were conducted at baseline and at the end of the 12-week intervention by a trained researcher following standardized protocols. Body weight was measured using a calibrated digital scale (Seca, Hamburg, Germany) to the nearest 0.5 kg, with participants wearing light clothing and no shoes. Height was recorded barefoot to the nearest 0.1 cm using a stadiometer. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Triceps skinfold thickness (TSF) was measured on the left arm's posterior-medial site using a skinfold caliper, taking the average of three readings spaced 15 s apart. Mid-arm circumference (MAC) was measured at the midpoint between the acromion and olecranon process using a non-stretch tape. Mid-arm muscle circumference (MAMC) was estimated by subtracting the product of TSF and π (3.1416) from MAC (MAMC = MAC – [3.1416 × TSF]).
Physical activity measurements
The Physical Activity record (see supplementary S2) was utilized to assess participants' physical activity levels over two separate days, including one weekday and one weekend day, during the week prior to the study and at week 12.
Nutritional status measurements
Nutritional status and malnutrition severity were assessed using the RFH-GA questionnaire, a validated tool specifically designed for patients with liver cirrhosis [20]. To our knowledge, no formal Persian version validation has yet been published. The RFH-GA incorporates clinical features such as BMI, mid-arm muscle circumference (MAMC), and dietary intake adequacy to classify malnutrition severity. In accordance with the questionnaire's algorithm, participants’ BMI was initially evaluated to determine whether it fell below or above the threshold of 20. Subsequently, mid-arm muscle circumference (MAMC) was calculated and compared to the 5th percentile. Finally, their dietary intake was assessed using food records. Due to the lack of published percentile charts for MAMC in Iranian patients with liver cirrhosis, reference percentile values were adapted from an international study [22].
Biochemical analysis measurements
Clinical biochemical parameters were measured by collecting 10 mL of fasting venous blood samples at baseline and study completion. Samples were centrifuged at 3500 rpm for 10 min to separate the serum and were promptly kept at − 70 °C until carrying out the analysis. Serum levels of total bilirubin, creatinine, albumin, and total protein were measured using enzymatic colorimetric methods with the BT1500 analyzer and reagents from Bayerx Fars Company. The international normalized ratio (INR) was calculated from prothrombin time (PT) using the formula:
 |
Severity of liver disease was quantitatively assessed using the MELD score, calculated with the formula:
 |
Higher MELD scores indicate more advanced liver dysfunction and higher short-term mortality risk [6].
Statistical analyses
Data analysis was performed using SPSS software version 27 (IBM Corp., Armonk, NY, USA). Quantitative variables with normal distribution were expressed as mean ± standard error (SE), while non-normally distributed quantitative variables were reported as median with interquartile range (IQR). Qualitative variables were presented as frequency and percentage. The normality of continuous variables was assessed using the Kolmogorov–Smirnov test and Q-Q plot.
Between-group comparisons for qualitative variables were conducted using the chi-square test. For quantitative variables with normal distribution, the independent samples t-test was applied, whereas for non-normal and ordinal variables, the Mann–Whitney U test was employed. To compare adjusted means between intervention and control groups, analysis of covariance (ANCOVA) was used, adjusting for baseline values. Prior to conducting ANCOVA, the underlying statistical assumptions were assessed. The homogeneity of regression slopes was examined by testing the interaction between the independent variable (group) and the covariate (baseline values). The normality of residuals was evaluated using the Kolmogorov–Smirnov test and visual inspection of Q-Q plots. Homogeneity of variances was assessed using Levene's test. These diagnostic checks confirmed that the assumptions were reasonably met for the analyses performed. All continuous variables, including biomarkers, were found to be approximately normally distributed; therefore, no data transformations were applied. Logistic regression models were conducted for the ordinal qualitative variable and adjusted for baseline covariates. Baseline measurements were included as covariates to control for initial differences between groups. Within-group comparisons (pre- and post-intervention) were performed using paired t-tests for normally distributed variables and Wilcoxon signed-rank tests for non-normally distributed variables. Statistical analyses were conducted on a per-protocol basis, including only participants who completed the full 12-week intervention and demonstrated adequate dietary compliance. This approach was chosen to evaluate the true effect of the dietary intervention in adherent participants. No imputation was performed for missing data, as the four dropouts had no post-baseline measurements. A p-value less than 0.05 was considered statistically significant.
Results
Out of the 46 patients initially enrolled, 21 participants in the intervention group and 21 in the control group successfully completed the 12-week intervention period. Reasons for the four dropouts included non-compliance with the dietary protocol (n = 2 in the intervention group), hospitalization unrelated to the study (n = 1 in the control group), and loss to follow-up (n = 1 in the control group). The flow of participants through the study, including dropout reasons for each group, is depicted in Fig. 1.
Fig. 1.
Study flow diagram. Of 1,315 screened individuals, 320 had confirmed cirrhosis. After exclusions (n = 274), 46 patients were randomized to the vegetable- and dairy-based protein diet (n = 23) or standard diet (n = 23). During follow-up, 2 participants in the intervention group discontinued due to non-adherence, and 2 in the control group were lost (1 lost to follow-up, 1 hospitalized). Finally, 21 participants per group completed the trial and were included in the per-protocol analysis
Baseline characteristics
Baseline demographic and clinical characteristics were comparable between groups. There were no significant differences in age (55.23 ± 1.36 vs. 52.57 ± 1.75 years, p = 0.23), weight (80.09 ± 3.39 vs. 75.6 ± 2.6 kg, p = 0.20), sex distribution (66.7% male in both groups, p = 1.00), marital status, educational level, body mass index (28.34 ± 0.98 vs. 26.83 ± 0.62 kg/m2, p = 0.20), MELD score (9.24 ± 0.75 vs. 8.1 ± 0.82, p = 0.33), triceps skinfold thickness, mid-arm circumference, mid-arm muscle circumference, and physical activity level (all p > 0.05). The etiology of cirrhosis showed a significant difference, with more participants in the intervention group having Non-Alcoholic Steatohepatitis (NASH) compared to the control group (85.7% vs. 42.9%, p = 0.02) (Table 1).
Table 1.
Baseline characteristics of the study patients
| Variables | Vegetable and dairy protein-based diet (n = 21) |
Standard diet (n = 21) |
p-Value |
|---|---|---|---|
| Age (year) | 55.23 (1.36) | 52.57 (1.75) | 0.23 † |
| Weight (kg) | 80.09 (3.39) | 75.6 (2.6) | 0.2† |
| Sex | 1.00 ‡ | ||
| Male | 14 (66.7%) | 14 (66.7%) | |
| Female | 7 (33.3%) | 7 (33.3%) | |
| Marital status | 0.51 ‡ | ||
| Single | 1 (4.8) | 2 (9.5) | |
| Married | 19 (90.5) | 19 (90.5) | |
| Divorced | 0 (0) | 0 (0) | |
| Widowed | 1 (4.8) | 0 (0) | |
| Educational level | 0.51§ | ||
| Below Diploma | 10 (47.6) | 14 (66.7) | |
| Diploma | 7(33.3) | 4 (19) | |
| University Degree | 4 (19) | 3 (14.3) | |
| BMI (kg/m2) | 28.34 (0.98) | 26.83 (0.62) | 0.2 † |
| TSF (mm) | 20.9 (1.7) | 18.4 (1.8) | 0.32 † |
| MAC (cm) | 31.57 (0.8) | 29.61 (0.98) | 0.13 † |
| MAMC (cm) | 24.98 (0.75) | 23.82 (1.09) | 0.39 † |
| Physical activity (MET-h/day) | 26.01 (1.44) | 27.23 (1.88) | 0.63 † |
| Etiology of Cirrhosis (n, %) | 0.02 ¥ | ||
| HBV | 0 (0) | 3 (14.3) | |
| HCV | 1 (4.8) | 5 (23.8) | |
| NASH | 18 (85.7) | 9 (42.9) | |
| Cryptogenic | 2 (9.5) | 4 (19) | |
| Supplement intake | |||
| B vitamins | 8 (38.1%) | 5 (23.8%) | 0.31‡ |
| Vitamin D | 7 (35.7%) | 8 (38.1%) | 0.74‡ |
| Calcium | 5 (23.8%) | 4 (19%) | 0.7‡ |
| L carnitine | 3 (14.3%) | 1 (4.8%) | 0.29‡ |
| Zinc | 6 (28.6%) | 3 (14.3%) | 0.25‡ |
| Magnesium | 7 (33.3%) | 6 (28.6%) | 0.73‡ |
| Lactulose | 20 (95.2%) | 21 (100%) | 0.3‡ |
| Diuretics | 6 (28.6%) | 8 (38.1) | 0.74‡ |
| Child–Pugh | 5.8 (0.28) | 5.7 (0.24) | 0.79† |
| MELD score | 9.24 (0.75) | 8.14 (0.82) | 0.33† |
| Serum Bilirubin (mg/dL) | 1.48 (0.15) | 1.54 (0.34) | 0.83† |
| Serum Creatinine (mg/dL) | 0.88 (0.03) | 0.85 (0.03) | 0.53† |
| INR | 1.32 (0.05) | 1.29 (0.05) | 0.71† |
| Serum Albumin (g/dL) | 3.40 (0.1) | 3.52 (0.1) | 0.42† |
| Total Protein (g/dL) | 6.41 (0.11) | 6.64 (0.12) | 0.16† |
BMI Body mass index, TSF (cm) Triceps Skinfold Thickness, MAC (cm) Mid-Arm Circumference, Mid-Arm Muscle Circumference, MELD Model for End-Stage Liver Disease, INR International Normalized Ratio, HBV Hepatitis B virus, HCV Hepatitis C virus, NASH Nonalcoholic steatohepatitis
Data are expressed as mean (standard error) or number (percentage)
P-values indicating statistical significance (p < 0.05) are shown in bold
† Denotes analysis performed using the Independent t-test
‡ Denotes analysis performed using the Pearson chi-squared test
§ Denotes analysis performed using the Mann–Whitney U-test
¥ Denotes analysis performed using the Fisher's Exact Test
Dietary intake and compliance
At baseline, no statistically significant differences were observed between groups for daily energy intake or macronutrient composition. Following the 12-week dietary intervention, the vegetable- and dairy-based protein diet group demonstrated significant increases in dietary fiber intake (29.08 ± 2.28 vs. 22.18 ± 1.78 g/day, p = 0.01) and vegetable-based protein intake (58.54 ± 4.18 vs. 41.45 ± 2.68 g/day, p = 0.001) relative to the standard diet group. Additionally, a significant reduction in animal-based protein intake was observed in the intervention group post-intervention (15.45 ± 3.03 vs. 33.23 ± 2.46 g/day, p < 0.001). The standard diet group showed a statistically significant decrease in total fat intake after 12 weeks (p = 0.02), whereas no significant changes were noted for energy, carbohydrates, or total protein intake in either group (Table 2).
Table 2.
Daily dietary intakes of the study patients at baseline and after the 12-wk intervention
| Variables |
Vegetable and dairy protein-based diet (n = 21) |
Standard diet (n = 21) |
p-Value | |
|---|---|---|---|---|
| Energy (kcal/day) | Before | 2067.5 (106.12) | 2073.06 (106.89) | 0.97 † |
| After | 2063.95 (90.46) | 1942.27 (75.85) | 0.11 ‡ | |
| p-value § | 0.96 | 0.06 | ||
| Carbohydrates (g/day) | Before | 274.86 (14.48) | 270.02 (16.63) | 0.82 † |
| After | 285.53 (12.38) | 251.92 (9.71) | 0.06 ‡ | |
| p-value § | 0.38 | 0.82 | ||
| Total fat in (g/day) | Before | 76.17 (5.01) | 79.68 (4.45) | 0.6 † |
| After | 73 (4.27) | 71.87 (3.93) | 0.5 ‡ | |
| p-value § | 0.52 | 0.02 | ||
| Fiber (g/day) | Before | 21.16 (1.82) | 21.97 (1.72) | 0.75 † |
| After | 29.08 (2.28) | 22.18 (1.78) | 0.01 ‡ | |
| p-value § | 0.001 | 0.93 | ||
| Protein (g/day) | Before | 84.64 (5.49) | 80.41 (4.65) | 0.4 † |
| After | 86.34 (4.3) | 85.41 (3.45) | 0.08 ‡ | |
| p-value § | 0.55 | 0.15 | ||
| Vegetable-based protein (g/day) | Before | 39.41 (3.18) | 37.21 (3.34) | 0.63 † |
| After | 58.54 (4.18) | 41.45 (2.68) | 0.001 ‡ | |
| p-value § | < 0.001 | 0.27 | ||
| Dairy-based protein (g/day) | Before | 7.15 (1.15) | 8.02 (1.47) | 0.4 † |
| After | 13.66 (1.28) | 10.72 (1.46) | 0.08 ‡ | |
| p-value § | < 0.001 | 0.11 | ||
| Animal-based protein (g/day) | Before | 38.06 (4.56) | 32.97 (3.29) | 0.37 † |
| After | 15.45 (3.03) | 33.23 (2.46) | < 0.001 ‡ | |
| p-value § | < 0.001 | 0.94 | ||
Data are expressed as mean (standard error of mean)
P-values indicating statistical significance (p < 0.05) are shown in bold
† Denotes analysis performed using the Independent t-test
‡ Denotes analysis performed using the Analysis of covariance (ANCOVA) adjusted for baseline values
§ Denotes analysis performed using the Paired t-test
The dietary compliance in the intervention group, assessed by the percentage of protein intake derived from vegetable-based and dairy sources relative to total daily protein intake, indicated an overall adherence rate of 83.6% ± 10.05%. Caloric compliance, measured as the percentage of calories consumed relative to the prescribed caloric intake, averaged 86.5% ± 7.67% in the intervention group and 89.2% ± 6.9% in the control group.
Biochemical parameters and MELD Score
Pre-intervention values of serum bilirubin, creatinine, INR, MELD score, serum albumin, and total protein were not significantly different between groups (Table 1). Post-intervention analysis revealed a significant decrease in MELD score in the vegetable- and dairy-based protein diet group (−1.17 ± 0.51, p = 0.03) whereas the standard diet group exhibited a significant increase in MELD score (0.70 ± 0.25, p = 0.01). Serum creatinine decreased significantly in the intervention group after the intervention (−0.05 ± 0.02 mg/dL, p = 0.01) but showed no significant change in the control group (0.02 ± 0.02 mg/dL, p = 0.37). Other biochemical parameters showed no significant within-group changes except for total protein, which decreased significantly in the intervention group (−0.25 ± 0.11, p = 0.03). It is important to note that despite this statistically significant decrease, the mean post-intervention total protein level in the intervention group remained within the normal clinical range (6.0–8.3 g/dL). Serum bilirubin, INR, and serum albumin did not exhibit statistically significant changes within either group.
Between-group comparisons of mean changes (crude model) showed that the intervention group had a significantly greater reduction in MELD score compared to the control group with a mean between group difference of −1.87 (95% CI: −3.03 to −0.71, p < 0.01). Similarly, the decrease in serum creatinine was significantly larger in the intervention group than in controls (mean difference −0.04, 95% CI: −0.14 to −0.01, p = 0.02). In addition, the intervention group showed a significant improvement in INR compared to the control group, with the between-group difference in change reaching statistical significance (mean difference −0.10, 95% CI: −0.17 to −0.02, p = 0.01). No significant between-group differences were observed for serum bilirubin, serum albumin, or total protein, indicating that these markers remained stable across groups.
Adjusted post-intervention means, controlling for baseline values, confirmed these findings with significant differences favoring the vegetable- and dairy-based diet group in MELD score (p < 0.01), serum creatinine (p = 0.02), and INR (p = 0.01). No significant between-group differences were observed for serum bilirubin, albumin, or total protein after adjustment (Table 3).
Table 3.
MELD and serum biochemical parameters in patients with liver cirrhosis in the study groups before and after the intervention
| Variable | Time | Vegetable- and Dairy-Based Protein Diet Group (n = 21) | Standard Diet Group (n = 21) | Between-group diff (95% CI) | P-between** | Adjusted between group diff (95% CI) | P- adjusted ** |
|---|---|---|---|---|---|---|---|
| MELD score | Baseline | 9.24 ± 0.75 | 8.14 ± 0.82 | −1.87 (−3.03 to −0.71) | < 0.01 | −1.62 (−2.69 to −0.55) | < 0.01 |
| After 12-week | 8.07 ± 0.53 | 8.84 ± 0.86 | |||||
| Within-group change (95% CI) | −1.17 (−2.23 to −0.11) | + 0.70 (0.18 to 1.22) | |||||
| P-within* | 0.03 | 0.01 | |||||
| Serum Bilirubin (mg/dL) | Baseline | 1.48 ± 0.15 | 1.54 ± 0.34 | −0.08 (−0.27 to 0.11) | 0.43 | −0.08 (−0.27 to 0.10) | 0.35 |
| After 12-week | 1.38 ± 0.13 | 1.52 ± 0.30 | |||||
| Within-group change (95% CI) | −0.10 (−0.27 to 0.07) | −0.02 (−0.14 to 0.10) | |||||
| P-within* | 0.25 | 0.68 | |||||
| Serum Creatinine (mg/dL) | Baseline | 0.88 ± 0.03 | 0.85 ± 0.03 | −0.07 (−0.13 to −0.01) | 0.02 | −0.07 (−0.13 to −0.01) | 0.02 |
| After 12-week | 0.82 ± 0.02 | 0.87 ± 0.04 | |||||
| Within-group change (95% CI) | −0.05 (−0.09 to −0.01) | + 0.02 (−0.02 to 0.06) | |||||
| P-within* | 0.01 | 0.37 | |||||
| INR | Baseline | 1.32 ± 0.05 | 1.29 ± 0.05 | −0.10 (−0.17 to −0.03) | 0.01 | −0.08 (−0.14 to −0.01) | 0.01 |
| After 12-week | 1.26 ± 0.03 | 1.32 ± 0.05 | |||||
| Within-group change (95% CI) | −0.06 (−0.13 to 0.01) | + 0.03 (0.01 to 0.05) | |||||
| P-within* | 0.11 | 0.05 | |||||
| Serum Albumin (g/dL) | Baseline | 3.40 ± 0.1 | 3.52 ± 0.1 | −0.06 (−0.25 to 0.13) | 0.54 | −0.10 (−0.29 to 0.08) | 0.28 |
| After 12-week | 3.34 ± 0.09 | 3.53 ± 0.09 | |||||
| Within-group change (95% CI) | −0.06 (−0.23 to 0.11) | + 0.01 (−0.11 to 0.13) | |||||
| P-within* | 0.46 | 0.95 | |||||
| Total Protein (g/dL) | Baseline | 6.41 ± 0.11 | 6.64 ± 0.12 | −0.21 (−0.49 to 0.07) | 0.13 | −0.31 (−0.56 to −0.06) | 0.01 |
| After 12-week | 6.16 ± 0.08 | 6.6 ± 0.12 | |||||
| Within-group change (95% CI) | −0.25 (−0.48 to −0.02) | −0.04 (−0.21 to 0.13) | |||||
| P-within* | 0.03 | 0.69 |
Data are presented as Mean ± standard error of mean or Mean (95% CI)
MELD Model for End-Stage Liver Disease, INR International Normalized Ratio, CI Confidence interval
*P-within values represent paired t-test results for pre-post comparisons within each group
**Between-group comparisons of mean change conducted using independent t-tests
***Post-intervention group means were compared using analysis of covariance (ANCOVA) adjusted for baseline values
P-values indicating statistical significance (p < 0.05) are shown in bold
Malnutrition status
At baseline, the majority of patients in each group were classified as well-nourished (85.7% intervention vs. 71.4% control, p = 0.26). Post-intervention, a nonsignificant reduction in the proportion of well-nourished patients was observed in both groups (71.4% intervention vs. 61.9% control). The prevalence of moderate malnutrition increased in both groups without reaching statistical significance. No cases of severe malnutrition were recorded during the study period.
Between-group differences in nutritional status categories were not statistically significant (Table 4). Additionally, no significant changes were observed in other anthropometric parameters, including weight, BMI, TSF, MAC, or MAMC, between or within groups before and after the intervention (Appendix Table).
Table 4.
Malnutrition severity in patients with liver cirrhosis in the study groups before and after the intervention
| Variable | Vegetable- and Dairy-Based Protein Diet Group (n = 21) | P value* | Standard Diet Group (n = 21) | P value* | P value** | ||
|---|---|---|---|---|---|---|---|
| Before | After | Before | After | ||||
| Well-nourished | 18 (85.7) | 15 (71.4) | 0.08 | 15 (71.4) | 13 (61.9) | 0.4 |
0.26a 0.9b |
| Moderate Malnutrition | 3 (14.3) | 6 (28.6) | 6 (28.6) | 8 (38.1) | |||
| Severe Malnutrition | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |||
Data are presented as number (%)
*Within-group comparison of malnutrition severity before and after intervention was performed using the Wilcoxon signed-rank test
**Comparison of malnutrition severity between the two groups at baseline and study end was performed using the Mann–Whitney U test (a) and a binary logistic regression model adjusted for baseline values (b)
P-values indicating statistical significance (p < 0.05) are shown in bold
Safety and tolerability
No serious adverse events related to the dietary intervention occurred. One control participant was hospitalized for elective hernia repair and withdrawn. No episodes of hepatic encephalopathy, gastrointestinal bleeding, or acute kidney injury were observed during the study period. However, we did not systematically collect data on gastrointestinal symptoms (e.g., bloating, flatulence, abdominal discomfort) as part of the study protocol.
Discussion
This randomized controlled trial is, to the best of our knowledge, among the first to directly evaluate the effects of a diet emphasizing vegetable and dairy-based proteins compared to an isocaloric, isonitrogenous standard diet in patients with liver cirrhosis. In this 12-week randomized controlled trial, a diet based on vegetable and dairy proteins significantly improved MELD score, serum creatinine, and INR compared to a standard isocaloric, isonitrogenous diet in patients with cirrhosis. Importantly, these improvements occurred without deterioration in nutritional status or serum albumin, addressing key clinical concerns regarding the safety of plant-based dietary modifications in this population.
During the 12-week intervention, energy, carbohydrate, and fat intakes did not differ significantly, but the intake of protein from vegetable and dairy sources, and fiber in the intervention group increased significantly, while animal-based protein intake decreased. This modification in protein sources may improve the amino acid profile and metabolic outcomes [16, 23–25]. Notably, the combination of vegetable and dairy protein intake within the intervention group did not result in a decrease in overall macronutrient or energy intake, thereby alleviating concerns posited regarding potential dietary inadequacy or poor adherence associated with such dietary modifications. Adherence to the prescribed diet based on calorie intake was satisfactory, with rates of 86% in the intervention group compared to 89% in the control group, further supporting the feasibility and acceptability of this balanced protein regimen in patients with liver cirrhosis.
The MELD score, a well-validated composite index used to predict short-term mortality and assess disease severity in cirrhosis, decreased by approximately 1.87 points in the intervention group compared to control group after 12-week intervention. This reduction in MELD score observed in the intervention group, accompanied by significant decreases in serum creatinine and improvement in INR (with no changes in bilirubin), represents the core finding of this trial. The simultaneous significant reduction in serum creatinine further underscores enhanced renal function, an important prognostic factor given the high burden of renal impairment and hepatorenal syndrome in cirrhotic patients. Improved INR reflects better hepatic synthetic function and coagulation status, indicating a reduced risk of bleeding complications. While the mechanisms underlying the observed improvements cannot be determined from this study, several hypotheses based on existing literature warrant consideration. First, vegetable and dairy protein sources typically contain higher ratios of branched-chain amino acids (BCAA) to aromatic amino acids (AAA) compared to animal proteins. This altered amino acid profile may reduce ammonia production and improve nitrogen balance, potentially contributing to the observed improvement in renal function (reflected by decreased creatinine) [26, 27]. Second, the significant increase in dietary fiber intake in the intervention group may have modulated the gut microbiome, potentially reducing endotoxin translocation and systemic inflammation, which could decrease hepatocyte loss severity [28–31]. Third, vegetable and dairy protein sources are richer in certain micronutrients with anti-inflammatory properties, including magnesium, polyphenols, and isoflavones [32–34]. However, as we did not measure inflammatory markers, amino acid profiles, gut microbiome composition, or specific micronutrient status, these mechanisms remain speculative and require investigation in future studies designed to test these pathways directly. The improvement in MELD score observed in our intervention group is consistent with findings from Maharshi et al., who demonstrated that a dietary regimen providing 30–35 kcal/kg and 1–1.5 g/kg ideal body weight per day from vegetable and casein-based dairy proteins, along with 2 g salt daily, significantly improved MELD score in patients with minimal hepatic encephalopathy compared to no nutritional intervention [19]. In contrast to our results, a cross-sectional study conducted among cirrhotic patients found no significant association between MELD score and tertiles of vegetable and dairy protein intake or animal protein tertiles [35]. While the observed reduction in MELD score is modest, it may be clinically relevant. Previous research, such as a cohort study, has shown that larger reductions in MELD score (greater than 3 points) are associated with improved short-term prognosis [36]. The smaller, yet significant, improvement seen in our study over a short 12-week period is encouraging and suggests a potential benefit of the dietary intervention. Importantly, adjusted analyses controlling for baseline differences reinforced these results, indicating that the observed improvements are attributable to the dietary intervention rather than confounding variable. Taken together, these findings provide robust evidence that modifying protein sources toward vegetable- and dairy-based proteins confers measurable clinical benefit in liver cirrhosis management. However, longer-term studies are required to determine if such changes translate into sustained improvements in clinical outcomes, such as reduced hospitalizations or mortality.
The improvement in INR observed in the intervention group warrants cautious interpretation. No participants were taking anticoagulant medications that could have influenced INR independently of liver function. Although vegetable and dairy protein-based diets are rich in vitamin K—a key nutrient for coagulation factor synthesis—and vitamin K deficiency is common in cirrhosis [37], we did not assess dietary vitamin K intake or serum vitamin K levels in this study. As such, any explanation involving vitamin K remains speculative. Alternative mechanisms, such as reduced systemic inflammation, improved hepatic synthetic function, or decreased portal pressure, may also contribute to improved coagulation status [38–40].
Malnutrition is a common and serious complication in patients with liver cirrhosis, leading to increased risks of complications, hospitalizations, and mortality, and it significantly worsens clinical outcomes and survival. The RFH-GA integrates key clinical parameters such as BMI, mid-arm muscle circumference (MAMC), and dietary intake adequacy to provide a comprehensive evaluation of nutritional status and malnutrition severity. With regard to adequate protein and calorie intake, no significant changes in anthropometric indices such as weight, BMI, TSF, MAC, or MAMC, nor in malnutrition numbers and severity scores between intervention and control, were detected between or within groups. This stability in nutritional status is clinically important because it directly addresses the major concern that a vegetable- and dairy-based protein diet might exacerbate malnutrition in cirrhotic patients, and confirms that the observed improvements in MELD score were not achieved at the expense of nutritional deterioration. Our findings align with previous findings emphasizing the importance of longer-term or multimodal nutrition and exercise interventions for marked muscle mass and function improvements [41, 42]. Randomized controlled trials investigating nutritional interventions in cirrhosis provide mixed evidence regarding improvements in anthropometric parameters. For instance, Maharshi et al. demonstrated significant improvements in MAC and muscle mass with a diet rich in vegetable and dairy proteins, but without meaningful changes in TSF or body fat, in patients with minimal hepatic encephalopathy [19]. Similarly, Les et al. showed that BCAA supplementation alongside a standard diet improved MAMC but did not influence other anthropometric measures [43]. Manguso et al. showed increased MAMC with a controlled diet emphasizing protein and complex carbohydrates, but no significant weight changes [44]. These studies highlight that interventions improving muscle mass may require longer durations or combined nutrition and exercise strategies to effect measurable changes in body composition. In patients with liver cirrhosis, multiple factors intricately contribute to the development of malnutrition. These factors include inadequate energy and protein intake, accelerated starvation, alcohol consumption, metabolic disturbances such as malabsorption and altered nutrient metabolism, hypermetabolism, gut microbiome dysbiosis, and hormonal imbalances. Moreover, elevated levels of inflammatory mediators like the pro-inflammatory cytokines IL-6 and TNF-α not only negatively affect appetite and limit adequate caloric intake [45] but also exacerbate sarcopenia through disruption of the mTOR signaling pathway [46–48]. Diets based on vegetable and dairy proteins, possessing anti-inflammatory and antioxidant properties, may help prevent this progression [31, 49–51]. Additionally, by improving the amino acid profile and increasing the ratio of BCAAs—which play critical roles in protein synthesis, energy production, and ammonia detoxification [52]—such diets can contribute to lowering ammonia levels, enhancing albumin synthesis [53], and possibly promoting fat storage [54].
Importantly, concerns persist among clinicians that adherence to vegetable- and dairy-based protein diets in cirrhotic patients may be challenging due to gastrointestinal discomfort and high fiber content, potentially worsening malnutrition. Our results, demonstrating stable nutritional status with satisfactory dietary adherence and no exacerbation of malnutrition markers, suggest that such diets can be safe and feasible in this population when appropriately designed and monitored. Altogether, these findings advocate for the inclusion of high-quality vegetable and dairy protein sources in nutritional management of liver cirrhosis. However, given the complex etiology of malnutrition in cirrhosis, future studies should explore longer-term interventions incorporating combined nutrition and exercise therapies, with advanced assessments of body composition and functional outcomes, to optimize nutritional rehabilitation.
Serum albumin levels, a critical but complex marker of hepatic synthetic ability and nutritional status, remained unchanged post-intervention. Given albumin’s multifactorial regulation, including effects of inflammation and fluid balance, these findings are not unexpected. The decrease in total serum protein observed in the intervention group, despite stable albumin levels is of uncertain clinical significance. This likely reflects a reduction in the globulin fraction. Globulins—particularly immunoglobulins and acute-phase proteins—are frequently elevated in cirrhosis due to chronic inflammation and systemic immune activation [55, 56]. This interpretation is consistent with the concurrent improvements in MELD score which collectively suggest overall clinical improvement. However, as globulin fractions or inflammatory markers were not directly measured, this explanation remains hypothetical. Measurement variability or normal biological fluctuation cannot be ruled out. Importantly, the between-group difference was not significant (p = 0.13), and values remained within normal range, indicating no clinically meaningful nutritional deterioration. In the absence of studies with identical interventions, we reviewed related studies investigating similar interventions. In a longitudinal intervention study involving 21 patients with liver cirrhosis supplemented with BCAA over 48 weeks, serum albumin levels did not change significantly after the intervention [57]. Furthermore, in another study, supplementation with 4 g BCAA three times daily for six months showed no positive effect on serum albumin and total protein compared to controls [58]. Whereas, a pilot prospective double-blind randomized trial on cirrhotic patients with sarcopenia found a significant improvement trend in albumin levels in the BCAA group; however, the difference between BCAA and placebo groups was not statistically significant, and no significant changes were observed in total serum protein in either group [59]. Conversely, some studies have reported positive effects of dietary intervention on serum protein levels [19, 60]. Contrary to these studies, our study patients received isocaloric diets with equal energy and macronutrients in both groups, which may explain the lack of significant albumin change. Manguso et al. investigated the effects of a controlled diet emphasizing complex carbohydrates (55%), protein (16% including 10% vegetable and 6% animal protein), and fat (28–30%) for 3 months followed by a free diet on protein-energy malnutrition and clinical outcomes in HCV-related cirrhosis. Serum albumin significantly increased during the controlled diet but returned to baseline after the free diet period [44]. In liver cirrhosis, progressive destruction of hepatocytes leads to a 60 to 80 percent reduction in albumin synthesis, which is associated with worsening liver function and disease prognosis. Additionally, vasodilation and activation of neurohumoral systems result in sodium and water retention, increasing plasma volume and diluting albumin concentration [61]. Oxidative stress and chronic inflammation also impair the structure and function of albumin. Furthermore, malnutrition and protein deficiency negatively affect albumin synthesis. As mentioned before, albumin levels do not directly reflect nutritional status, as they are influenced by stress and hepatic functional capacity. However, albumin concentrations can be used to identify patients at higher risk of malnutrition, since stressors such as inflammation, trauma, and injury may accelerate nutrient depletion [62].
From a clinical perspective, these findings suggest that replacing animal protein with vegetable and dairy protein sources may represent a feasible nutritional strategy for patients with compensated cirrhosis. Given the improvement in MELD score without evidence of worsening nutritional status, clinicians may consider emphasizing vegetable and dairy protein sources when designing individualized dietary plans, particularly for patients concerned about disease progression or intolerance to animal proteins.
This study has several limitations that should be considered when interpreting the results. First, the modest sample size and relatively short 12-week intervention period may have limited our ability to detect subtle or longer-term changes, particularly in anthropometric outcomes and nutritional status categories. Second, the lack of blinding of participants and dietitians, while inherent to dietary intervention studies, introduces the potential for performance bias. Outcome assessors, laboratory personnel, and statisticians remained blinded to group allocation. Third, dietary intake and compliance were assessed using self-reported dietary records, which are subject to recall bias and social desirability bias. To minimize this bias, participants received standardized training and all records were reviewed with a dietitian within 48 h of completion. A more objective measure, such as urinary nitrogen balance, would have been preferable but was not feasible in this outpatient setting. Fourth, the presence of edema in some cirrhotic patients may have affected the accuracy of anthropometric measurements such as weight, despite our efforts to account for this. However, Measurements were performed by the same trained assessor using standardized procedures. Fifth, the analysis of categorical malnutrition status was limited by small subgroup sizes, reducing statistical power. It is important to note as a limitation that, to our knowledge, no formally validated Persian version of the RFH-GA exists. Furthermore, due to the absence of published MAMC percentile charts specific to the Iranian population, particularly for those with liver cirrhosis, we were obliged to use reference values from an international study. Furthermore, the exclusion of patients with advanced cirrhosis (MELD > 18 or Child–Pugh class C), while necessary for safety and protocol adherence, limits the generalizability of our results to this more vulnerable patient population. Future research should incorporate extended follow-up with comprehensive evaluations includi ng molecular biomarkers to clarify therapeutic efficacy.
Conclusion
In conclusion, adherence to a 12-week diet based on vegetable and dairy protein in patients with compensated cirrhosis was associated with modest improvements in MELD score, primarily driven by decreases in serum creatinine and INR, without measurable deterioration in nutritional status or serum albumin. These findings suggest that modifying protein source toward vegetable and dairy proteins may be a safe and potentially beneficial component of nutritional management in this population. However, given the modest sample size, and short intervention duration, these results should be considered hypothesis-generating. Longer-term studies with larger samples and hard clinical endpoints are needed to determine whether these biochemical improvements translate into reduced morbidity and mortality.
Recommendations and future directions
Although the observed changes in malnutrition among participants were not statistically significant, the increasing trend over time warrants close long-term monitoring. Prolonged interventions are necessary to determine if the short-term improvements in MELD score are sustained and translate into reduced morbidity and mortality. If funding permits, adherence monitoring should rely on urinary nitrogen measurements rather than dietary records to enhance accuracy. Finally, while our findings support the safety and feasibility of this dietary approach, future studies should continue to monitor gastrointestinal tolerance and patient-reported outcomes to optimize dietary counseling and adherence, particularly in populations with limited access to diverse protein sources.
Supplementary Information
Acknowledgements
We gratefully acknowledge the invaluable support and cooperation of all participants who volunteered for this study. Our sincere thanks go to the clinical and administrative staff of the gastroenterology clinics at Tehran University of Medical Sciences (TUMS) for their assistance in patient recruitment and data collection. We also thank the funding bodies and institutions that facilitated this work. Their support was essential for the successful completion of this trial.
Authors’ contributions
S.A., M.S., and M.T. assisted with the study conception and design; B.Kh-R. and M.T. contributed to the compilation of data; M.T., A.O. and B.Kh-R. Contributed to manuscript drafting; M.T. conducted data analysis; A.O. contributed to the interpretation of data and revising of the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This study has been funded and supported by Tehran university of medical sciences (TUMS); Grant no. 1402–2-212–66625.
Data availability
Data can be obtained from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
The ethics committee of the Tehran University of Medical Sciences approved this study (IR.TUMS.MEDICINE.REC.1402.060) which was performed in compliance with the principles of the Declaration of Helsinki. Prior to the study enrollment, written informed consent was obtained from all patients.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
Data can be obtained from the corresponding author upon reasonable request.