Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease, is defined as liver steatosis in the presence of at least one cardiometabolic risk factor and the absence of harmful alcohol intake. The current global prevalence of MASLD is approximately 30%1. In the Middle East, prevalence rates can reach up to 40%, and among patients with type 2 diabetes mellitus (T2DM), MASLD affects up to 70%2,3. A recent nationwide study from Turkiye reported a MASLD prevalence of 70%, with 30% of these patients having advanced fibrosis according to FIB-4 scoring4. Given these findings, data on the prevalence and severity of MASLD in patients with T2DM are available globally and regionally. However, data specific to Türkiye remains limited.
Steatotic liver disease is a major cause of liver-related morbidity and mortality. MASLD begins with simple fatty liver disease and eventually leads to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma5. Obesity, insulin resistance, and T2DM are common risk factors for progressive liver disease in MASLD. Patients with T2DM have a higher prevalence of MASLD and related morbidity6. MASLD is the leading chronic liver disease today and is predicted to be the most common cause of chronic liver disease in the future. That’s why early diagnosis and management is very important.
Studies showing the prevalence of MASLD in T2DM patients are very few. Non-invasive imaging modalities and serum tests combined non-invasive scores, which have become very popular in the evaluation of liver diseases in the last decade, are becoming increasingly important in detecting MASLD and liver fibrosis in T2DM patients. Our aim in the study is to investigate the frequency of MASLD in patients with T2DM using non-invasive evaluation methods and to reveal the relationship between complications of diabetes mellitus and steatotic liver and liver fibrosis in these patients.
Methods
In this single-center study, 504 adults (≥ 18 years old) T2DM patients who consecutively attended the diabetes mellitus outpatient clinic at Istanbul Faculty of Medicine, who did not have other causes of liver disease, were examined. MASLD was evaluated prospectively with non-invasive scoring based on biochemical tests and FibroScan®.
Inclusion criterias: (1) to have T2DM, (2) to be ≥ 18 years old.
Exclusion criterias: (1) to have another chronic liver disease, (2) alcohol consumption > 20 g/day in women and > 30 g/day in men, (3) to have a secondary cause for hepatic steatosis.
Demographic characteristics, T2DM duration, T2DM complications (microvascular-macrovascular), presence of other criteria of metabolic syndrome (blood pressure, lipid profile, waist circumference), laboratory values, non-invasive fibrosis scoring tests based on biochemical tests, and Fibroscan® measurements of the patients were examined. Hypertension was defined as systolic blood pressure > 130 mmHg or diastolic blood pressure > 85 mmHg or using antihypertensive drugs. Dyslipidemia was defined as triglyceride level > 150 mg/dl or HDL level < 40 mg/dl in men, < 50 mg/dl in women or the use of lipid-lowering agents (statin or fenofibrate).
Diagnostic criteria for T2DM: HbA1c ≥ 6.5% or fasting plasma glucose (fasting referring to no caloric intake for ≥ 8 h) ≥ 126 mg/dl or 2-h plasma glucose during oral glucose tolerance test ≥ 200 mg/dl or treatment for type 2 diabetes7.
In FibroScan® measurements; controlled attenuation parameter (CAP) score ≥ 275 dB/m was considered as liver steatosis (S1 ≥ 275, < 290 dB/m, S2 ≥ 290, < 302 dB/m, S3 ≥ 302 dB/m); liver stiffness measurement (LSM) ≥ 8.0 kPa was considered as clinically significant fibrosis (F2-4), ≥ 12 kPa was considered as advanced fibrosis (F3-4), and ≥ 15 kPa was considered as cirrhosis (F4).
MASLD was defined by FibroScan® CAP score ≥ 275 dB/m without any other chronic liver disease or secondary cause for hepatic steatosis in T2DM patients.
FAST (FIBROSCAN- AST) Score (< 0.35, ≥ 0.35–< 0.67, ≥ 0.67; low-, intermediate-, and high-risk groups for clinically significant fibrosis)8, Agile 3 + score (< 0.45, ≥ 0.45–≤ 0.68, > 0.68; low-, intermediate-, and high-risk groups for advanced fibrosis)9, Agile 4 (< 0.251, ≥ 0.251–≤ 0.565, > 0.565; low-, intermediate-, and high-risk groups for cirrhosis)10, Fibrotic NASH index (≤ 0.1, > 0.1–< 0.33, ≥ 0.33; low-, intermediate-, and high-risk groups for fibrosis)11, Fatty Liver Index (< 30, ≥ 30–< 60, ≥ 60; low-, intermediate-, and high-risk groups for MASLD)12, Hepatic steatosis index (> 36; high risk for MASLD)13, FIB-4 (< 1.3, ≥ 1.3–<2.67, ≥ 2.67; low-, intermediate-, and high-risk groups for fibrosis)14, NAFLD Fibrosis Score (< − 1.455, > 0.675; low-, and high risk for fibrosis)15, APRI (< 0.5, ≥ 0.5–< 1.5, ≥ 1.5; low-, intermediate-, and high-risk groups for fibrosis)16, HEPAMET Fibrosis Score (< 0.12, ≥ 0.12–≤ 0.47, > 0.47; low-, intermediate-, and high-risk groups for fibrosis)17, were examined as non-invasive scores based on biochemical tests.
Microvascular complications of T2DM (nephropathy, neuropathy, and retinopathy) were examined. Nephropathy was evaluated according to spot urine total protein/creatinine ratio and eGFR level. Nephropathy was defined as microalbuminuria ≥ 30 mg/day according to the spot urine total protein/creatinine ratio or eGFR < 60 ml/min/1.73 m2 for at least 3 months. The presence of neuropathy was accepted in patients with neuropathy symptoms or receiving drug therapy for neuropathy. All patients with retinopathy were diagnosed with retinopathy as a result of an ophthalmologist examination. The presence of coronary artery disease, cerebrovascular disease, peripheral artery disease, and diabetic foot wounds were examined as macrovascular complications.
Approval for this study was obtained from the Ethics Committee of Istanbul University, Istanbul Faculty of Medicine on 11/03/2022. The protocol number is 2022/348. All the applied procedures complied with the ethical standards of the Human Testing Committee of our institution and the Helsinki Declaration. The written informed consent was obtained from the patients. To protect personal data in the study, each patient was given a number, and their identity was concealed.
Statistical analysis
In the descriptive statistics of the data, the mean, standard deviation, and median (IQR 25–75) were used. Categorical variables were expressed as numbers (n) and percentages (%). Independent samples t-test was used to analyze quantitative independent data. The chi-square test was used to analyze independent qualitative data. Pearson’s correlation test was used to determine the strength and direction of the relationship between two continuous variables. Survival curves were estimated using the Kaplan–Meier method, and compared using the log-rank test. Multivariate analysis was performed based on the Cox proportional hazards regression model. The results were evaluated at a 95% confidence interval and significance level of p < 0.05. Data analysis was performed using SPSS version 22.0.
Results
Demographic and biochemical features of the patients
There were 504 patients with T2DM in the study. 273 (54.2%) were female and 231 (45.8%) were male. The mean age was 60.5 ± 10.6 [median 62, IQR (25–75) (54–68)] years. The mean disease age was 153.2 ± 104.2 [median 144, IQR (25–75) (72–204)] months. The mean weight of the patients was 80.8 ± 16.3 [median 80, IQR (25–75) (70–90)] kg, the mean height was 164.1 ± 9.6 [median 164, IQR (25–75) (157 − 170)] cm, the mean BMI was 30 ± 5.7 [median 29.3, IQR (25–75) (26.2–33.7)] kg/m2, the mean waist circumference was 105.8 ± 12.8 [median 105, IQR (25–75) (97–114)] cm, the mean hip circumference was 110.6 ± 13.5 [median 110, IQR (25–75) (101–120)] cm, the mean systolic blood pressure was 131.4 ± 20.3 [median 130, IQR (25–75) (120–140)] mmHg, the mean diastolic blood pressure was 79.4 ± 11.7 [median 80, IQR (25–75) (70–87)] mmHg. 388 (77%) patients had hypertension, and 429 (85.1%) had dyslipidemia. 244 (48.4%) patients used insulin, and 290 (57.5%) used lipid-lowering agents. According to BMI, 175 (34.7%) patients were overweight (25–29.9 kg/m2), 197 (39.1%) patients were obese (30–39.9 kg/m2), and 31 (6.2%) patients were morbidly obese (≥ 40 kg/m2). The mean HbA1c of the patients was 7.6% ± 1.8% (3.9 − 16.1%) [median 7.1%, IQR (25–75) (6.3 − 8.4%)], and the mean fasting blood sugar was 156 ± 65 mg/dl. According to FibroScan® measurements, the mean CAP value of the patients was 275 ± 53.8 [median 275 dB/m, IQR (25–75) (235–317)] dB/m and the mean LSM value was 9.4 ± 10.7 [median 6.3 kPa, IQR (25–75) (4.9–9)]. Demographic characteristics, biochemical values, fibroscan results, and non-invasive scores of all patients are shown in Table 1.
Table 1. Baseline characteristics of all patients (n = 504).
Demographic features | |
|---|---|
Female (n, %) | 273 (54.2) |
Age (year) (mean ± SD) | 60.5 ± 10.6 |
T2DM duration (month) (mean ± SD) | 153.2 ± 104.2 |
Height (cm) (mean ± SD) | 164.1 ± 9.6 |
Weight (kg) (mean ± SD) | 80.8 ± 16.3 |
BMI (kg/m2) (mean ± SD) | 30 ± 5.7 |
Over-weight (25–29.9 kg/m2) (n, %) | 175 (34.7) |
Obese (30–39.9 kg/m2) (n, %) | 197 (39.1) |
Morbid obese (≥ 40 kg/m2) (n, %) | 31 (6.2) |
Waist circumference (cm) (mean ± SD) | 105.8 ± 12.8 |
Hip circumference (cm) (mean ± SD) | 110.6 ± 13.5 |
Systolic Blood Pressure (mmHg) (mean ± SD) | 131.4 ± 20.3 |
Diastolic Blood Pressure (mmHg) (mean ± SD) | 79.4 ± 11.7 |
Hypertension (n, %) | 388 (77) |
Dyslipidemia (n, %) | 429 (85.1) |
Biochemical features | |
HbA1c (%) (mean ± SD) | 7.6 ± 1.8 |
Fasting blood sugar (mg/dl) (mean ± SD) | 156 ± 65 |
Total cholesterol (mg/dl) (mean ± SD) | 179 ± 50 |
LDL (mg/dl) (mean ± SD) | 106 ± 43 |
HDL (mg/dl) (mean ± SD) | 45 ± 15 |
Triglyceride (mg/dl) (mean ± SD) | 185 ± 172 |
AST (U/L) (mean ± SD) | 23 ± 21 |
ALT (U/L) (mean ± SD) | 26 ± 31 |
ALP (U/L) (mean ± SD) | 89 ± 50 |
GGT (U/L) (mean ± SD) | 38 ± 58 |
Total protein (g/dl) (mean ± SD) | 7.2 ± 1 |
Albumin (g/dl) (mean ± SD) | 4.4 ± 0.5 |
AFP (ng/ml) (mean ± SD) | 2.8 ± 2.1 |
Total Bilirubin (mg/dl) (mean ± SD) | 0.5 ± 0.8 |
Platelet (103/µl) (mean ± SD) | 262 ± 88 |
INR (mean ± SD) | 1 ± 0.3 |
Creatinine (mg/dl) (mean ± SD) | 0.9 ± 0.5 |
eGFR (ml/min/1.73 m2) (mean ± SD) | 85.7 ± 24.5 |
Uric acid (mg/dl) (mean ± SD) | 5.2 ± 1.6 |
Proteinuria (g/day) (mean ± SD) | 0.1 ± 0.3 |
Non-invasive scores | |
FAST Score (mean ± SD) | 0.2 ± 0.2 |
Agile3 + (mean ± SD) | 0.5 ± 0.3 |
Agile 4 (mean ± SD) | 0.1 ± 0.2 |
Fibrosis NASH Index (mean ± SD) | 0.3 ± 0.3 |
Fatty Liver Index (mean ± SD) | 67 ± 26.9 |
Hepatic Steaosis Index (mean ± SD) | 42 ± 8.1 |
FIB-4 (mean ± SD) | 1.3 ± 1 |
NAFLD Fibrosis Score (mean ± SD) | − 0.7 ± 1.6 |
APRI (mean ± SD) | 0.3 ± 0.3 |
Hepamet Fibrosis Score (mean ± SD) | 0.2 ± 0.2 |
CAP (dB/m) (mean ± SD) | 275 ± 53.8 |
LSM (kPa) (mean ± SD) | 9.4 ± 10.7 |
MASLD (CAP ≥ 275 dB/m) (n, %) | 252 (50) |
S1 (CAP ≥ 275, < 290 dB/m) | 49 (9.7) |
S2 (CAP ≥ 290, < 302 dB/m) | 38 (7.5) |
S3 (CAP ≥ 302 dB/m) | 165 (32.7) |
Clinically significant fibrosis (F ≥ 8 kPa, F2-4) (n, %) | 154 (30.6) |
Advanced fibrosis ( F ≥ 12, F3-4) (n, %) | 68 (13.5) |
Cirrhosis (F ≥ 15 kPa, F4) (n, %) | 58 (11.5) |
Diabetic complications | |
Microvascular complications (n, %) | 344 (68.3) |
Nephropathy (n, %) | 206 (40.9) |
Retinopathy (n, %) | 93 (18.5) |
Neuropathy (n, %) | 183 (36.3) |
Macrovascular complications (n, %) | 182 (36.1) |
Coronary artery disease (n, %) | 156 (31) |
Peripheral artery disease (n, %) | 33 (6.5) |
Cerebrovascular events (n, %) | 22 (4.4) |
Diabetic foot infection (n, %) | 17 (3.4) |
T2DM: Type 2 Diabetes Mellitus; BMI: Body Mass Index; LDL: Low Density Lipoprotein; HDL: High Density Lipoprtein; AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase; ALP: Alkaline Phosphatase; GGT: Gamma-glutamyl Transferase; AFP: Alpha-Fetoprotein; INR: International Normalized Ratio; eGFR: Estimated Glomerular Filtration Rate; FIB-4: Fibrosis 4 Score; NAFLD: Non-alcoholic Fatty Liver Disease; APRI: AST to Platelet Ratio Index; FAST: Fibroscan-AST; CAP: Controlled Attenuation Parameter; LSM: Liver Stiffness Measurement; S: Steatosis; F: Fibrosis.
Fibroscan results and non-invasive scores
All results of the non-invasive scores of all patients and MASLD patients are given in Tables 2 and 3, respectively.
Table 2. MASLD and fibrosis risk distribution of patients according to non-invasive scores in all patients (n = 504).
Median (IQR 25–75) | Low-risk (n, %) | Intermediate-risk (n, %) | High-risk (n, %) | |
|---|---|---|---|---|
FAST (< 0.35, ≥ 0.35–< 0.67, ≥ 0.67) | 0.063 (0.02–0.20) | 421 (83.5) | 51 (10.1) | 32 (6.4) |
Agile 3 + (< 0.45, ≥ 0.45–≤ 0.68, > 0.68) | 0.41 (0.22–0.67) | 275 (54.6) | 109 (21.6) | 120 (23.8) |
Agile 4 (< 0.251, ≥ 0.251–≤ 0.565, > 0.565) | 0.02 (0.01–0.09) | 440 (87.3) | 33 (6.5) | 31 (6.2) |
Fibrotic NASH index (≤ 0.1, > 0.1–< 0.33, ≥ 0.33) | 0.17 (0.08–0.38) | 160 (31.7) | 194 (38.5) | 150 (29.8) |
Fatty Liver Index (< 30, ≥ 30–< 60, ≥ 60) | 74.7 (45.6–90.3) | 63 (12.5) | 124 (24.6) | 317 (62.9) |
Hepatic Steatosis Index (≤ 36, > 36) | 41.3 (37.2–46.5) | 103 (20.4) | 401 (79.6) | |
NAFLD fibrosis (< − 1.455, > 0.675) | − 0.8 (− 1.6–0.2) | 153 (30.4) | 83 (16.5) | |
HEPAMET (< 0.12, ≥ 0.12–≤ 0.47, > 0.47) | 0.1 (0.1–0.2) | 273 (54.2) | 190 (37.7) | 41 (8.1) |
FIB-4 (< 1.3, ≥ 1.3–< 2.67, ≥ 2.67) | 1.0 (0.7–1.5) | 354 (70.2) | 115 (22.8) | 35 (7) |
APRI (< 0.5, ≥ 0.5–< 1.5, ≥ 01.5) | 0.2 (0.1–0.3) | 454 (90.1) | 43 (8.5) | 7 (1.4) |
FAST: Fibroscan-AST; NAFLD: Non-alcoholic Fatty Liver Disease; FIB-4: Fibrosis 4 Score; APRI: AST to Platelet Ratio Index.
Table 3. MASLD and fibrosis risk distribution of patients according to non-invasive scores in MASLD patients (n = 252).
Median (IQR 25–75) | Low-risk (n, %) | Intermediate-risk (n, %) | High-risk (n, %) | |
|---|---|---|---|---|
FAST (< 0.35, ≥ 0.35–< 0.67, ≥ 0.67) | 0.1 (0.04–0.40) | 189 (75) | 39 (15.5) | 24 (9.5) |
Agile 3 + (< 0.45, ≥ 0.45–≤ 0.68, > 0.68) | 0.43 (0.23–0.69) | 133 (52.8) | 54 (21.4) | 65 (25.8) |
Agile 4 (< 0.251, ≥ 0.251–≤ 0.565, > 0.565) | 0.03 (0.01–0.10) | 218 (86.4) | 17 (6.8) | 17 (6.8) |
Fibrotic NASH index (≤ 0.1, > 0.1–< 0.33, ≥ 0.33) | 0.19 (0.10–0.45) | 73 (29) | 92 (36.5) | 87 (34.5) |
Fatty Liver Index (< 30, ≥ 30–< 60, ≥ 60) | 86.4 (67.6–95.6) | 11 (4.5) | 39 (15.5) | 202 (80.2) |
Hepatic Steatosis Index (≤ 36, > 36) | 44.6 (40–49.2) | 23 (9.1) | 229 (90.9) | |
NAFLD fibrosis (< -1.455, > 0.675) | − 0.8 (− 1.8–0.1) | 86 (34.1) | 38 (15.1) | |
HEPAMET (< 0.12, ≥ 0.12–≤ 0.47, > 0.47) | 0.10 (0.09–0.21) | 149 (59.1) | 82 (32.6) | 21 (8.3) |
FIB-4 (< 1.3, ≥ 1.3–< 2.67, ≥ 2.67) | 0.9 (0.7–1.3) | 191 (75.8) | 44 (17.5) | 17 (6.7) |
APRI (< 0.5, ≥ 0.5–< 1.5, ≥ 1.5) | 0.2 (0.1–0.3) | 221 (87.7) | 27 (10.7) | 4 (1.6) |
FAST: Fibroscan-AST; NAFLD: Non-alcoholic Fatty Liver Disease; FIB-4: Fibrosis 4 Score; APRI: AST to Platelet Ratio Index.
According to Pearson’s correlation test LSM was most significantly correlated with Agile 4 and FAST scores (p < 0.01, r = 0.813; p < 0.01, r = 0.652, respectively), CAP score was most significantly correlated with fatty liver index and hepatic steatosis index (p < 0.01, r = 0.501; p < 0.01, r = 0.404, respectively).
The characteristics of MASLD patients.
252 (50%) of the patients had CAP ≥ 275 dB/m and had MASLD according to FibroScan® measurements. 144 (52.7%) of MASLD patients were female. The mean age of MASLD patients was 58.6 ± 10.0 years. When MASLD patients were evaluated in detail, 49 (19.4%) patients had grade I steatosis (S1) (CAP ≥ 275, < 290 dB/m), 38 (15.1%) patients had grade II steatosis (S2) (CAP ≥ 290, < 302 dB/m), 165 (65.5%) patients had grade III steatosis (S3) (CAP ≥ 302 dB/m). It was observed that as the degree of steatosis in the patients increased, the frequency of clinically significant fibrosis increased significantly (p = 0.162, p = 0.013, and p < 0.001, respectively, for comparing S0 with S1, S2, and S3) (Fig. 1a). BMI, waist, and hip circumference were higher in patients with CAP ≥ 275 dB/m, and these patients were younger (the mean age of MASLD patients was 58.6 ± 10.0 years, and the mean age of non-MASLD patients was 62.4 ± 10.9 years, p < 0.001) and had shorter T2DM duration (the T2DM duration of MASLD patients was 141.1 ± 97.7 months, and the mean T2DM duration of non-MASLD patients was 165.4 ± 109.3 months, p = 0.009). It was observed that the frequency of MASLD increased significantly as BMI increased in patients (p < 0.001, for comparing normal weight with overweight, obese, and morbidly obese) (Fig. 1b). In the MASLD group, HDL level was lower (p = 0.002); triglyceride, AST, and ALT levels were higher (p = 0.011, p = 0.043, and p = 0.011, respectively). FAST score, Fibrotic NASH index, Fatty liver index, Hepatic steatosis index, CAP, and LSM were significantly higher in MASLD patients (p < 0.001, p = 0.003, p < 0.001, p < 0.001, p < 0.001, and p = 0.027, respectively). The comparison of demographic characteristics, biochemical values, fibroscan results, and non-invasive scores of patients with and without MASLD is shown in Table 4.
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Fig. 1
(a) As the degree of steatosis in the patients increased, the frequency of clinically significant fibrosis increased significantly. (b) It was observed that the frequency of MASLD increased significantly as BMI increased in patients.
Table 4. Comparison of demographic characteristics, biochemical values, and non-invasive scores of patients without and with MASLD.
Demography | No-MASLD (n = 252, CAP < 275 dB/m) | MASLD (n = 252, CAP ≥ 275 dB/m) | p-value |
|---|---|---|---|
Age (year) | 62.3 ± 10.8 | 58.6 ± 10.0 | < 0.001 |
Gender | |||
Female (n, %) | 129 (51.2) | 144 (57.1) | 0.180 |
Male (n, %) | 123 (48.8) | 108 (42.9) | |
T2DM duration (month) (mean ± SD) | 165.4 ± 109.3 | 141.1 ± 97.7 | 0.009 |
Height (cm) (mean ± SD) | 164.2 ± 9.5 | 164.0 ± 9.8 | 0.840 |
Weight (kg) (mean ± SD) | 74.7 ± 12.9 | 87 ± 17 | < 0.001 |
BMI (kg/m2) (mean ± SD) | 27.7 ± 4.7 | 32.3 ± 5.8 | < 0.001 |
Weist circumference (cm) (mean ± SD) | 101.2 ± 11.4 | 110.4 ± 12.3 | < 0.001 |
Hip circumference (cm) (mean ± SD) | 106.9 ± 10.8 | 114.4 ± 14.8 | < 0.001 |
Systolic Blood Pressure (mmHg) (mean ± SD) | 130.5 ± 22.5 | 132.3 ± 17.9 | 0.436 |
Diastolic Blood Pressure (mmHg) (mean ± SD) | 78.5 ± 12.3 | 80.2 ± 11 | 0.187 |
Hypertension (n, %) | 190 (75.4) | 198 (78.6) | 0.397 |
Dyslipidemia (n, %) | 206 (81.7) | 223 (88.5) | 0.033 |
Biochemistry | No-MASLD (n = 252, CAP < 275 dB/m) | MASLD (n = 252, CAP ≥ 275 dB/m) | p-value |
Fasting blood sugar (mg/dl) (mean ± SD) | 151.5 ± 70.0 | 160.0 ± 58.3 | 0.140 |
HbA1c (%)(mean ± SD) | 7.5 ± 1.9 | 8.2 ± 9.8 | 0.320 |
Total cholesterol (mg/dl) (mean ± SD) | 177 ± 52 | 181 ± 49 | 0.330 |
LDL (mg/dl) (mean ± SD) | 103 ± 42 | 108 ± 44 | 0.228 |
HDL (mg/dl) (mean ± SD) | 47 ± 15 | 43 ± 14 | 0.002 |
Triglyceride (mg/dl) (mean ± SD) | 166 ± 167 | 205 ± 175 | 0.011 |
AST (U/L) (mean ± SD) | 21 ± 19 | 25 ± 23 | 0.043 |
ALT (U/L) (mean ± SD) | 23 ± 32 | 30 ± 29 | 0.011 |
ALP (U/L) (mean ± SD) | 90 ± 62 | 87 ± 33 | 0.463 |
GGT (U/L) (mean ± SD) | 33 ± 46 | 42 ± 67 | 0.072 |
Total bilirubin (U/L) (mean ± SD) | 0.5 ± 0.8 | 0.5 ± 0.9 | 0.766 |
Direct bilirubin (U/L) (mean ± SD) | 0.2 ± 0.7 | 0.2 ± 0.1 | 0.287 |
Total protein (g/dl) (mean ± SD) | 7.1 ± 0.6 | 7.3 ± 1.1 | 0.018 |
Albumin (g/dl) (mean ± SD) | 4.4 ± 0.5 | 4.5 ± 0.5 | 0.057 |
AFP (ng/ml) (mean ± SD) | 3.1 ± 2.7 | 2.6 ± 1.1 | 0.247 |
Platelet (103/µl) (mean ± SD) | 254 ± 84 | 271 ± 92 | 0.030 |
INR (mean ± SD) | 1 ± 0.2 | 1 ± 0.3 | 0.551 |
Creatinine (mg/dl) (mean ± SD) | 0.9 ± 0.6 | 0.81 ± 0.4 | 0.011 |
eGFR (ml/min/1.73 m2) (mean ± SD) | 82.2 ± 27.1 | 89.1 ± 21.1 | 0.002 |
Uric acid (mg/dl) (mean ± SD) | 5.2 ± 1.7 | 5.2 ± 1.6 | 0.896 |
Proteinuria (g/day) (mean ± SD) | 0.1 ± 0.2 | 0.2 ± 0.4 | 0.341 |
Scores | No-MASLD (n = 252, CAP < 275 dB/m) | MASLD (n = 252, CAP ≥ 275 dB/m) | p-value |
FAST Score (mean ± SD) | 0.1 ± 0.2 | 0.2 ± 0.3 | < 0.001 |
Agile 3 + (mean ± SD) | 0.4 ± 0.3 | 0.5 ± 0.3 | 0.284 |
Agile 4 (mean ± SD) | 0.1 ± 0.2 | 0.1 ± 0.2 | 0.427 |
Fibrotic NASH index (mean ± SD) | 0.2 ± 0.2 | 0.3 ± 0.3 | 0.003 |
Fatty liver index (mean ± SD) | 55.9 ± 26.6 | 78.3 ± 22.1 | < 0.001 |
Hepatic steatosis index (mean ± SD) | 39.3 ± 8.0 | 45 ± 7.0 | < 0.001 |
NAFLD fibrosis score (mean ± SD) | − 0.6 ± 1.5 | -0.8 ± 1.7 | 0.311 |
HEPAMET (mean ± SD) | 0.2 ± 0.2 | 0.2 ± 0.2 | 0.167 |
FIB-4 (mean ± SD) | 1.3 ± 0.9 | 1.2 ± 1.1 | 0.216 |
APRI (mean ± SD) | 0.3 ± 0.4 | 0.3 ± 0.3 | 0.448 |
CAP (dB/m) (mean ± SD) | 230 ± 30 | 319 ± 30 | < 0.001 |
LSM (kPa) (mean ± SD) | 8.3 ± 10.8 | 10.5 ± 10.5 | 0.027 |
T2DM: Type 2 Diabetes Mellitus; BMI: Body Mass Index; LDL: Low Density Lipoprotein; HDL: High Density Lipoprtein; AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase; ALP: Alkaline Phosphatase; GGT: Gamma-glutamyl Transferase; AFP: Alpha-Fetoprotein; INR: International Normalized Ratio; eGFR: Estimated Glomerular Filtration Rate; FIB-4: Fibrosis 4 Score; NAFLD: Non-alcoholic Fatty Liver Disease; APRI: AST to Platelet Ratio Index; FAST: Fibroscan-AST; CAP: Controlled Attenuation Parameter; LSM: Liver Stiffness Measurement; MASLD: Metabolic Dysfunction–Associated Liver Disease.
According to Kaplan-Meier analysis, the MASLD rate was significantly lower in patients using insulin and anti-hyperlipidemic agents (p < 0.001 and p = 0.017, respectively).
According to the multivariate Cox regression test, obesity (HR = 2.003; 95% CI = 1.553–2.583; p < 0.001), and dyslipidemia (HR = 1.785; 95% Cl = 1.159–2.748; p = 0.009) are significantly related to being MASLD, and MASLD was significantly lower in those using insulin and lipid-lowering agents (HR = 0.418; 95% CI = 0.322–0.544; p = 0.000, and HR = 0.741; 95% CI = 0.559–0.983; p = 0.037, respectively) (Table 5). There was no association between HbA1c and steatosis and fibrosis stages (p = 0.751 and p = 0.562).
Table 5. Multivariate Cox regression analysis of the factors related to MASLD.
Steatosis HR (95% CI) | p-value | |
|---|---|---|
Obesity | 2.003 (1.553 – 2.583) | < 0.001 |
Dyslipidemia | 1.785 (1.159 – 2.748) | 0.009 |
Insulin | 0.418 (0.322 – 0.544) | < 0.001 |
Anti-hyperlipidemic agent | 0.741 (0.559 – 0.983) | 0.037 |
CI: Confidence interval; HR: Hazard ratio.
The model included obesity (BMI ≥ 30 kg/m2), dyslipidemia, insulin, and anti-hyperlipidemic agents which were found to be significantly related to MASLD in survival analyses.
The characteristics of clinically significant fibrosis patients
In all patients, 154 (30.6%) had clinically significant fibrosis (LSM ≥ 8 kPa), 68 (13.5%) patients had advanced fibrosis (LSM ≥ 12), and 58 (11.5%) patients had cirrhosis (LSM ≥ 15 kPa) according to FibroScan® measurements. In those with LSM ≥ 8 kPa, BMI, waist, and hip circumference were higher, and T2DM duration was shorter (p < 0.001, p < 0.001, p < 0.001, and p = 0.002, respectively). In the clinically significant fibrosis (LSM ≥ 8 kPa) group, liver enzymes (AST, ALT, ALP, GGT), bilirubin, INR, and proteinuria levels were significantly higher, and platelet levels were significantly lower (p < 0.001, p < 0.001, p = 0.018, p < 0.001, p = 0.011, p = 0.015, p = 0.024, and p < 0.001, respectively). All non-invasive scores examined were significantly higher in patients with clinically significant fibrosis (LSM ≥ 8 kPa) (p < 0.001 for all scores except hepatic steatosis index, and p = 0.002 for hepatic steatosis index).
In the MASLD group, 103 (40.9%) patients had clinically significant fibrosis, 43 (17.1%) patients had advanced fibrosis, and 35 (13.9%) patients had cirrhosis according to fibroscan measurements. The comparison of demographic characteristics, biochemical values, and non-invasive scores of MASLD patients with and without clinically significant fibrosis (LSM ≥ 8 kPa) is shown in Table 6. As seen in Table 6, AST, ALT, ALP, GGT, bilirubin and INR levels were higher, while platelet levels were lower in patients with clinically significant fibrosis (p < 0.001, p < 0.001, p = 0.023, p < 0.001, p = 0.044, p = 0.036, and p = 0.001, respectively).
Table 6. Comparison of demographic characteristics, biochemical values, and non-invasive scores of MASLD patients without and with clinically significant fibrosis (F ≥ 8 kPa).
Demography | No or minimal fibrosis (F0-1) (n = 147, < 8 kPa) | Clinically significant fibrosis (F2-4) (n = 105, ≥ 8 kPa) | p-value |
|---|---|---|---|
Age (year) (mean ± SD) | 58.8 ± 10.5 | 58.3 ± 9.4 | 0.667 |
Gender | |||
Female (n, %) | 87 (59.2) | 57 (54.3) | 0.439 |
Male (n, %) | 60 (40.8) | 48 (45.7) | |
T2DM duration (month) (mean ± SD) | 151.4 ± 106.9 | 126.7 ± 81.6 | 0.038 |
Height (cm) (mean ± SD) | 163.7 ± 9.6 | 164.6 ± 10.1 | 0.444 |
Weight (kg) (mean ± SD) | 84 ± 16 | 91.1 ± 17.3 | 0.001 |
BMI (kg/m2) (mean ± SD) | 31.4 ± 5.7 | 33.6 ± 5.8 | 0.004 |
Waist circumference (cm) (mean ± SD) | 108.6 ± 12.4 | 113 ± 12 | 0.005 |
Hip circumference (cm) (mean ± SD) | 112.7 ± 14.2 | 116.7 ± 15.5 | 0.036 |
Systolic Blood Pressure (mmHg) (mean ± SD) | 132 ± 18.3 | 131 ± 17.2 | 0.652 |
Diastolic Blood Pressure (mmHg) (mean ± SD) | 80 ± 11.4 | 81 ± 10.3 | 0.348 |
Hypertension (n, %) | 111 (75.5) | 87 (82.9) | 0.161 |
Dyslipidemia (n, %) | 106 (72.1) | 69 (65.7) | 0.277 |
Biochemistry | No or Minimal Fibrosis (F0-1) (n = 147, < 8 kPa) | Clinically Significant fibrosis (F2-4) (n = 105, ≥ 8 kPa) | p-value |
Fasting blood sugar (mg/dl) (mean ± SD) | 157 ± 55 | 165 ± 63 | 0.309 |
HbA1c (%)(mean ± SD) | 7.5 ± 1.6 | 7.8 ± 2 | 0.211 |
Total cholesterol (mg/dl) (mean ± SD) | 181 ± 49 | 183 ± 49 | 0.745 |
LDL (mg/dl) (mean ± SD) | 105 ± 37 | 111 ± 53 | 0.162 |
HDL (mg/dl) (mean ± SD) | 44 ± 15 | 42 ± 12 | 0.216 |
Triglyceride (mg/dl) (mean ± SD) | 190 ± 116 | 226 ± 233 | 0.104 |
AST (U/L) (mean ± SD) | 19 ± 11 | 33 ± 32 | < 0.001 |
ALT (U/L) (mean ± SD) | 23 ± 17 | 39 ± 39 | < 0.001 |
ALP (U/L) (mean ± SD) | 83 ± 27 | 93 ± 39 | 0.023 |
GGT (U/L) (mean ± SD) | 28 ± 32 | 63 ± 94 | < 0.001 |
Total bilirubin (U/L) (mean ± SD) | 0.4 ± 0.3 | 0.8 ± 1.4 | 0.044 |
Direct bilirubin (U/L) (mean ± SD) | 0.2 ± 0.1 | 0.2 ± 0.2 | < 0.001 |
Total protein (g/dl) (mean ± SD) | 7.2 ± 0.5 | 7.5 ± 1.8 | 0.253 |
Albumin (g/dl) (mean ± SD) | 4.5 ± 0.4 | 4.4 ± 0.6 | 0.419 |
AFP (ng/ml) (mean ± SD) | 2.1 ± 0.8 | 3.1 ± 1.3 | 0.005 |
Platelet (103/µl) (mean ± SD) | 287 ± 90 | 248 ± 89 | 0.001 |
INR (mean ± SD) | 0.9 ± 0.1 | 1.0 ± 0.5 | 0.036 |
Creatinine (mg/dl) (mean ± SD) | 0.8 ± 0.5 | 0.8 ± 0.3 | 0.734 |
eGFR (ml/min/1.73 m2) (mean ± SD) | 88 ± 21 | 90 ± 21 | 0.496 |
Uric acid (mg/dl) (mean ± SD) | 5.2 ± 1.6 | 5.2 ± 1.6 | 0.911 |
Proteinuria (g/d) (mean ± SD) | 0.1 ± 0.4 | 0.2 ± 0.5 | 0.279 |
Scores | No or minimal fibrosis (F0-1) (n = 147, < 8 kPa) | Significant fibrosis (F2-4) (n = 105, ≥ 8 kPa) | p-value |
FAST Score (mean ± SD) | 0.1 ± 0.1 | 0.4 ± 0.3 | < 0.001 |
Agile 3 + (mean ± SD) | 0.3 ± 0.2 | 0.7 ± 0.2 | < 0.001 |
Agile 4 (mean ± SD) | 0.03 ± 0.05 | 0.3 ± 0.3 | < 0.001 |
Fibrotic NASH index (mean ± SD) | 0.2 ± 0.2 | 0.4 ± 0.3 | < 0.001 |
Fatty liver index (mean ± SD) | 72.5 ± 24 | 86.4 ± 16 | < 0.001 |
Hepatic steatosis index (mean ± SD) | 44.2 ± 6.6 | 46 ± 7.6 | 0.053 |
NAFLD fibrosis score (mean ± SD) | − 1.1 ± 1.6 | − 0.3 ± 1.8 | < 0.001 |
HEPAMET (mean ± SD) | 0.1 ± 0.1 | 0.2 ± 0.2 | < 0.001 |
FIB-4 (mean ± SD) | 0.9 ± 0.6 | 1.6 ± 1.5 | < 0.001 |
APRI (mean ± SD) | 0.2 ± 0.1 | 0.4 ± 0.4 | < 0.001 |
CAP (dB/m) (mean ± SD) | 315 ± 30 | 326 ± 30 | 0.003 |
LSM (kPa) (mean ± SD) | 5.8 ± 1.1 | 17 ± 13.7 | < 0.001 |
T2DM: Type 2 Diabetes Mellitus; BMI: Body Mass Index; LDL: Low Density Lipoprotein; HDL: High Density Lipoprtein; AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase; ALP: Alkaline Phosphatase; GGT: Gamma-glutamyl Transferase; AFP: Alpha-Fetoprotein; INR: International Normalized Ratio; eGFR: Estimated Glomerular Filtration Rate; FIB-4: Fibrosis 4 Score; NAFLD: Non-alcoholic Fatty Liver Disease; APRI: AST to Platelet Ratio Index; FAST: Fibroscan-AST; CAP: Controlled Attenuation Parameter; LSM: Liver Stiffness Measurement.
According to Kaplan-Meier analysis, the clinically significant fibrosis rate was significantly lower in patients using insulin and anti-hyperlipidemic agents (p < 0.001 and p < 0.001, respectively) in MASLD patients.
Of the 252 MASLD patients, 61 (24.2%) had FIB-4 ≥ 1.3, and 40 of them (15.9%) had clinically significant fibrosis (LSM ≥ 8 kPa). Of the 252 MASLD patients, 191 (75.8%) had FIB-4 < 1.3, and 63 of them (25%) had clinically significant fibrosis (LSM ≥ 8 kPa). According to these results, 40.9% of MASLD patients had to be referred to a hepatologist for management.
Evaluation of ALT levels in MASLD patients
In 44 (17.5%) patients with MASLD, ALT > 42 U/L (our laboratory upper limit). In 18 (7.1%) of those without MASLD, ALT > 42 U/L was present. In patients with MASLD, the mean CAP score in those with ALT > 42 U/L was significantly higher than in those with normal ALT levels (mean CAP score in those with ALT < 42 U/L was 317.3 + 29.2 dB/m, in those with ALT > 42 U/L was 328.4 + 32.5 dB/m, p = 0.041).
In 149 of those with MASLD, clinically significant fibrosis was absent (LSM < 8 kPa), of whom 14 (9.4%) had ALT > 42 U/L. In 103 of those with MASLD, there was clinically significant fibrosis (LSM ≥ 8 kPa). Of these, 30 (29.1%) had ALT > 42 U/L. Of those with MASLD, 43 had advanced fibrosis (LSM ≥ 12 kPa), of whom only 12 (27.9%) had ALT > 42 U/L.
Complications
344 (68.5%) patients had microvascular complications. Microvascular complications, in order of frequency, were nephropathy in 206 (40.9%) patients, neuropathy in 183 (36.3%) patients, and retinopathy in 93 (18.5%) patients. 182 (36.1%) patients had macrovascular complications. Macrovascular complications, in order of frequency, were coronary artery disease in 156 (31%) patients, peripheral artery disease in 33 (6.5%) patients, cerebrovascular events in 22 (4.4%) patients, and diabetic foot wounds in 17 (3.4%) patients.
According to Kaplan-Meier survival analysis, microvascular complications were more common in MASLD patients (p = 0.006). Microvascular complications were examined by subdividing into nephropathy, neuropathy, and retinopathy. While there was a significant relationship between MASLD and nephropathy and neuropathy in survival analyses (p = 0.014 and p = 0.026, respectively), no relationship was found between MASLD and retinopathy (p = 0.829). According to Kaplan-Meier analysis, no significant relationship was found between MASLD and macrovascular complications (p = 0.197). There was no difference in macrovascular complications between patients with and without MASLD according to survival analyses (p = 0.197).
According to Kaplan-Meier analysis, a significant relationship was detected between clinically significant fibrosis and microvascular complications (p = 0.027) in MASLD patients. Microvascular complications were examined by subdividing into nephropathy, neuropathy, and retinopathy. While there was a significant relationship between clinically significant fibrosis and nephropathy in survival analyses (p = 0.035), no relationship was found between neuropathy and retinopathy (p = 0.080 and p = 0.146, respectively).
According to Kaplan-Meier analysis, a significant relationship was found between clinically significant fibrosis and macrovascular complications (p = 0.015) in MASLD patients. Macrovascular complications were examined by subdividing into coronary artery disease, peripheral artery disease, cerebrovascular events, and diabetic foot wound. While a significant relationship was found between clinically significant fibrosis and cerebrovascular events and peripheral artery disease (p = 0.009 and p = 0.012, respectively); no significant relationship was found in survival analyses between clinically significant fibrosis and coronary artery disease, and diabetic foot wound (p = 0.204 and p = 0.139, respectively).
Discussion
In this prospective study, we evaluated the prevalence of MASLD, clinically significant fibrosis, advanced fibrosis, and cirrhosis in adult T2DM patients by using non-invasive tests. Multiple studies have demonstrated that the prevalence of MASLD among patients with T2DM is approximately 70% (46−72%)6,18. In this study, we found the MASLD as 50% according to non-invasive tests. The prevalence of clinically significant fibrosis was found 16% in some studies19. However, in our study, this rate was found to be 30.6%. Although we found the rate of MASLD in our cohort of T2DM patients to be similar to the literature, we found the rate of clinically significant fibrosis to be higher than the literature. This shows that more study is needed in this area to be able to speak more definitively about the data.
Obesity is associated with an increased risk of disease progression in MASLD. The presence of obesity amplified the risk of liver steatosis and liver fibrosis in these patient groups20. In our study, the rates of both MASLD, clinically significant fibrosis, advanced fibrosis, and cirrhosis were found to be significantly higher in the obese patients than in the non-obese group.
It is known that the presence of hypertension and dyslipidemia is higher in patients with MASLD than in the normal population21. Additionally, hypertension and dyslipidemia are important risk factors for the development of cirrhosis and HCC in these patients22. In our study, there was no difference in liver steatosis and fibrosis between patients with and without hypertension, but a more steatotic liver was observed in patients with dyslipidemia, an important criterion of metabolic syndrome.
MASLD is associated with increased microvascular and macrovascular complications in T2DM patients23,24. However, there are very few studies comparing T2DM microvascular and macrovascular complications with liver steatosis and liver fibrosis head-to-head. In a study conducted in Italy, it was observed that diabetic nephropathy and retinopathy were almost twice as common in T2DM patients with MASLD compared to those without MASLD25. While the relationship between diabetic nephropathy and MASLD could be shown in some other studies26, the relationship between diabetic retinopathy and MASLD could not be shown in some studies27. In a case-control study, it was shown that the risk of diabetic neuropathy was increased in T2DM patients with MASLD during a 5-year follow-up28. In our study, we found a significant relationship between nephropathy and neuropathy with MASLD, but there was no relationship with retinopathy. Nephropathy was observed to be more common in patients with clinically significant fibrosis. Studies have shown that coronary artery disease and peripheral artery disease are more common in T2DM patients accompanied by MASLD29,30, but more studies are needed to demonstrate the relationship between cerebrovascular disease and diabetic foot wounds. In our study, no relationship was found between MASLD and macrovascular complications, but we found that there was a significant relationship between clinically significant fibrosis and cerebrovascular events.
We found that ALT was especially higher in patients with MASLD or clinically significant fibrosis. In a study conducted in the United States of America, ALT was significantly higher in T2DM patients with MASLD and ALT may be an important predictor of steatotic liver in T2DM patients (AUROC of 0.84 for ALT, with the confidence interval between 0.76 and 0.92 (p < 0.05)) has been shown31. The normal ALT level in patients with MASLD does not mean that there is no significant problem in the liver. ALT is normal in 2/3 of MASLD patients with clinically significant fibrosis.
Non-invasive modalities for determining steatosis and the grade of fibrosis are mainly based on the examination of serum tests or imaging methods like elastography. However, studies supporting the validity of these methods in the general population are still needed. In a study, it was shown that the FAST score was correlated with FIB-4 (r = 0.545; p < 0.01) and NAFLD (r = 0.400; p < 0.01) fibrosis score32. In our study, the correlation between many non-invasive scores and elastography values was examined. Agile 4 (p < 0.01, r = 0.813) and FAST (p < 0.01, r = 0.652) scores were the most common correlated with LSM, and fatty liver index (p < 0.01, r = 0.501) and hepatic steatosis index (p < 0.01, r = 0.404) were the most common correlated with CAP.
In adults with MASLD, a multi-step approach is recommended to examine liver fibrosis and to decide whether patients should be referred to a hepatologist or not33. Firstly, a blood-based score, such as FIB-4, should be used. After this step, liver elastography can be recommended as a second step to further clarify the fibrosis stage. When these two non-invasive methods are combined, approximately 40.9% of patients with MASLD require referral to a hepatologist for management, according to our study results.
We think that the strengths of this study include the use of multiple non-invasive diagnostic tests, the large sample size, and the limited availability of data from our country of origin.
Conclusion
Steatotic liver and fibrotic liver are highly common in patients with T2DM. These increase even more as BMI increases. As the severity of steatosis increases, fibrosis becomes advanced. The non-invasive tests that correlate best with FibroScan® measurements are FIB-4 and FAST scores for LSM, and ‘fatty liver index’ and ‘hepatic steatosis index’ for steatosis. According to the results of our study, approximately 40% of patients with T2DM and MASLD need to be referred to hepatologists because they have clinically significant fibrosis.
Author contributions
Z.İ., F.B., A.E.B., C.K., G.K., Z.İ., and İ.V.Ş. conceived and designed the study. Z.İ., K.N., A.R., S.G.U., H.H., K.K., and B.Ç. collected the data. Z.İ, A.Ç.Ö., F.A., K.D., F.B., and S.K. performed formal analyses. Z.İ, B.Ç, A.Ç.Ö, and S.K. drafted the manuscript. Z.İ, B.Ç, A.Ç.Ö, F.A, K.D, F.B, and S.K. reviewed the manuscript and contributed technically to the quality of the manuscript. S.K. provided supervision and administrative support. All authors reviewed and approved the final manuscript text.
Funding
No financial support.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Abstract
It was aimed to investigate the frequency of metabolic dysfunction–associated steatotic liver disease (MASLD) in type 2 diabetes mellitus (T2DM) patients with non-invasive tests. We prospectively evaluated the frequency of MASLD and fibrosis stage of the liver with biomarkers based on blood tests and FibroScan® in adult patients with T2DM who were followed up from the outpatient clinic in a tertiary center. Liver stiffness measurement (LSM) ≥ 8 kPa was accepted as clinically significant fibrosis (≥ F2), and ≥ 12 kPa was accepted as advanced fibrosis (F3-4) in FibroScan® measurements. The cut-off value of the CAP score was accepted as 275 dB/m for steatosis. There were 504 patients with T2DM in the study. 54.2% were female. 252 (50%) patients had MASLD. 30.6% had clinically significant fibrosis, and 13.5% had advanced fibrosis. The degree of steatosis in the patients increased, the frequency of clinically significant fibrosis increased (p < 0.05). The frequency of MASLD significantly increased as BMI increased (p < 0.05). Diabetic nephropathy and neuropathy were more common in MASLD patients (p < 0.05). There was a significant relationship between clinically significant fibrosis and nephropathy (p < 0.001). MASLD and significant liver fibrosis are highly common in patients with T2DM. As the severity of liver steatosis increases, fibrosis stage progresses.
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Details
; Bektaş, Fatih 2 ; Bardak, Ali Emre 3 ; Kızıltaş, Cansu 3 ; Kemeç, Gamze 3 ; İmanov, Ziya 1 ; Şenkal, İbrahim Volkan 1 ; Nuriyev, Kanan 1 ; Rustamzade, Aynura 1 ; Genç Uluçeçen, Sezen 1 ; Hacisahinogullari, Hülya 2 ; Karşıdağ, Kubilay 2 ; Çavuş, Bilger 1 ; Çifcibaşı Örmeci, Aslı 1 ; Akyüz, Filiz 1 ; Demir, Kadir 1 ; Beşışık, Fatih 1 ; Kaymakoğlu, Sabahattin 1 1 Istanbul University, Division of Gastroenterohepatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul, Türkiye (GRID:grid.9601.e) (ISNI:0000 0001 2166 6619)
2 Istanbul University, Division of Endocrinology and Metabolic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul, Türkiye (GRID:grid.9601.e) (ISNI:0000 0001 2166 6619)
3 Istanbul University, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul, Türkiye (GRID:grid.9601.e) (ISNI:0000 0001 2166 6619)