Abstract
Background
The current definition of lean is based on body mass index (BMI). However, BMI is an imperfect surrogate for adiposity and provides no information on central obesity (CO). Hence, we explored the differences in clinical profile and liver disease severity in lean patients with nonalcoholic fatty liver disease (NAFLD) with and without CO.
Methods
One hundred seventy lean patients with NAFLD (BMI <23 kg/m2) were divided into two groups depending upon the presence or absence of CO (waist circumference ≥80 cm in females and ≥90 cm in males). Noninvasive assessment of steatosis was done by ultrasound and controlled attenuation parameter (CAP), while fibrosis was assessed with FIB-4 and liver stiffness measurement (LSM). FibroScan-AST (FAST) score was used for non-invasive prediction of NASH with significant fibrosis.
Results
Of 170 patients with lean NAFLD, 96 (56.5%) had CO. Female gender (40.6% vs. 17.6%, P = 0.001), hypertriglyceridemia (58.3% vs. 39.2%, P = 0.01) and metabolic syndrome (23.9% vs. 4.1%, P < 0.001) were more common in the CO group. There was a poor correlation between BMI and waist circumference (r = 0.24, 95% CI: 0.09–0.38). Grade 2–3 steatosis on ultrasound was significantly more common in CO patients (30% vs. 12.3%, P = 0.007). CAP [312.5 (289.8–341) dB/m vs. 275 (248–305.1) dB/m, P = 0.002], FAST score [0.42 (0.15–0.66) vs. 0.26 (0.11–0.39), P = 0.04], FIB-4 and LSM were higher in those with CO. Advanced fibrosis was more prevalent among CO patients using FIB-4 (19.8% vs 8.1%, P = 0.03) and LSM (9.5% vs. 0, P = 0.04). CO was independently associated with advanced fibrosis after adjusting for BMI and metabolic risk factors (aOR: 3.11 (1.10–8.96), P = 0.03). Among these 170 patients, 142 fulfilled metabolic dysfunction associated steatotic liver disease (MASLD) criteria. CO was also an independent risk factor for advanced fibrosis in MASLD (3.32 (1.23–8.5), P = 0.02).
Conclusion
Lean patients with NAFLD or MASLD and CO have more severe liver disease compared to those without CO.
Keywords: NASH, MASLD, MAFLD, waist circumference, BMI
Nonalcoholic fatty liver disease (NAFLD) is one of the commonest causes of chronic liver disease globally and in India. Although most patients with NAFLD are obese or overweight, around one-fifth of the patients are lean with a normal body mass index (BMI).1,2 This phenotype is referred to as lean NAFLD. Current literature suggests that while metabolic co-morbidities like type 2 diabetes mellitus (T2DM) and hypertension (HTN) are more common in obese or overweight patients with NAFLD, liver disease severity is similar or slightly milder in lean NAFLD compared to nonlean patients.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 More importantly, lean NAFLD can progress to clinically significant liver disease and long-term clinical outcomes are similar between lean and non-lean patients with NAFLD.3,17, 18, 19
Currently, lean NAFLD is defined based on the presence of NAFLD in an individual with a normal BMI.20,21 However, BMI is an imperfect surrogate for adiposity. It is influenced by multiple factors, including muscularity and bone density.22,23 Further, BMI provides no information on body fat distribution, visceral adiposity, and central obesity. Clinical measures of central obesity provide a better assessment of visceral adipose tissue, which is more insulin resistant, prone to lipolysis, associated with proinflammatory adipokines, and intricately linked with the pathogenesis of NAFLD.24 Waist circumference is an easy-to-measure clinical marker for central obesity and has consistently been shown to outperform BMI as a predictor of metabolic and cardiovascular outcomes.25 Indeed, the recent guidance study by the Indian National Association for the Study of the Liver (INASL) has suggested that a normal weight circumference should be used in addition to normal BMI for defining lean NAFLD.26 However, it is not known whether exclusion of central obesity will help to better risk stratify lean patients with NAFLD. Hence, we planned to explore the difference in the clinical profile and liver disease severity in lean NAFLD with and without central obesity.
Although a recent Delphi consensus has suggested the use of metabolic dysfunction associated steatotic liver disease (MASLD), we have used the terminology of NAFLD in this study as this is a retrospective analysis of patients diagnosed with NAFLD in the past 12-years. However, we have also analyzed our data according to the MASLD criteria.27
Methods
In this cross-sectional observational study, data of all adult patients with NAFLD and normal BMI (<23 kg/m2) managed prospectively in a real-life fashion over the last 12 years (January 2011 till May 2023) at a tertiary academic center in north India was analyzed retrospectively. The diagnosis of NAFLD was established in the presence of hepatic steatosis inferred on ultrasound, controlled attenuation parameter (CAP) >248 dB/m or liver biopsy in the absence of significant alcohol consumption (less than 20 g/day) after excluding other causes of liver disease, including viral hepatitis, autoimmune liver disease, celiac disease, Wilson's disease, and hemochromatosis. Patients with incomplete data for calculating FIB-4, AST, or ALT levels more than 5 times of the upper limit of normal of 40 U/L, decompensated cirrhosis or hepatocellular carcinoma were excluded from the study. The study was approved by the institutional ethical committee and has been reported in accordance with the STROBE guidelines (11).
Demographic, clinical, and anthropometric data were retrieved from the patient's records. Waist circumference was measured at the midpoint between the top of the iliac crest and the last palpable rib were noted. Data of various investigations, including complete hemogram, liver function test, lipid and glycemic profile, hepatobiliary ultrasound (USG), and FibroScan [Echosens (Paris)] including CAP and liver stiffness measurement (LSM) were also recorded.
Definitions of Lean, Centrally Obese, Centrally Nonobese, and Other Metabolic Risk Factors
Lean was defined using Indian BMI cut-off of <23 kg/m2.28 Central obesity was defined as a waist circumference of ≥80 cm in females and ≥90 cm in males.28 Using these cut-offs, lean NAFLD patients were categorized into centrally obese (CO) and centrally nonobese (CNO) groups. We used the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria for defining metabolic syndrome and other risk factors, including type 2 diabetes mellitus (T2DM), hypertension (HTN), and dyslipidemia with modifications for waist circumference as mentioned above.
Noninvasive Assessment of Liver Disease Severity
Steatosis was assessed using USG (grade 1: hyperechoic liver; grade 2: obscured periportal echogenicity; grade 3: obscured diaphragmatic echogenicity) and CAP (S1: 248 to <268 dB/m; S2: 268 to <280 dB/m; S3: >280 dB/m).29 Significant elevation of AST and ALT was defined as levels higher than 2 times of the upper normal limit of 40 U/L. The FibroScan-AST (FAST) score which incorporates AST, CAP, and LSM was used for noninvasive assessment of NASH with significant fibrosis.30 Fibrosis was evaluated noninvasively with FIB-4 and LSM. Advanced fibrosis was ruled-out with a FIB-4 cut-off of <1.3 or LSM <8 kPa while it was ruled-in with a FIB-4 cut-off of >2.67 or LSM >12 kPa.31,32
Outcomes
Our primary outcome was the prevalence of advanced fibrosis using FIB-4 in lean NAFLD patients with and without CO. Secondary objectives included correlation between BMI and waist circumference, differences in demographics, metabolic profiles, liver biochemistry and noninvasive tests of steatosis, NASH, and fibrosis among lean NAFLD patients with and without CO, and the clinical risk factors for advanced fibrosis in lean NAFLD. A supplementary analysis of the same outcomes was also performed for those patients fulfilling MASLD criteria.27
Sample Size Calculation
There is no data available on the prevalence of advanced fibrosis in lean NAFLD, as stratified by the presence of CO. In the lean NAFLD population as a whole, advanced fibrosis has been estimated to be present in 10%–25% patients in several studies.21 Assuming a reasonable prevalence of advanced fibrosis among lean NAFLD patients of 17.5%, a minimum sample size of 169 patients is required to estimate such a proportion at a confidence level of 99% with precision of estimate 0.075.
Statistical Analysis
MedCalc® Statistical Software version 20.2 (MedCalc Software Ltd, Ostend, Belgium) and GraphPad Prism v9.3.1 (GraphPad Software, San Diego, California, USA) were used for statistical analysis and graphing. Quantitative data were expressed as mean ± standard deviation or median (interquartile range) with normality of data being evaluated using the D'Agostino-Pearson test and t-test or Mann–Whitney test (as applicable) was used for comparison. Qualitative data were expressed as percentages and was compared using chi square test or the Cochran–Armitage test for trend (as applicable). Correlation between waist circumference and BMI was assessed using Pearson's correlation coefficient (r) and trend lines in CO and CNO patients were plotted with LOESS smoothening. Multivariate logistic regression analysis for predictors of advanced fibrosis as ascertained by FIB-4 score of >2.67 was done by incorporating the variables of central obesity, BMI, T2DM, HTN, and dyslipidemia in a stepwise model where variables were entered into the model if P < 0.05 and removed if P > 0.1. Multicollinearity was assessed using variance inflation factors (VIF) with VIF >10 being considered suggestive of strong multicollinearity. All statistical tests were performed two-sided and P ≤ 0.05 was considered significant.
Results
One hundred and seventy lean patients with NAFLD fulfilled the eligibility criteria and were included in the study. The mean age of our study cohort was 37.76 ± 11.83 years, and most were males (69.4%). CO was present in 96 (56.5%) patients (CO group) and absent in 74 (43.5%) patients (CNO group).
Demographic and Metabolic Comorbidities
The clinico-demographic differences between CO and CNO groups are tabulated in Table 1. There was no difference in age between CO (39.2 ± 11.8 years) and CNO groups (35.8 ± 11.6, P = 0.07). Females were significantly more likely to have CO compared to males (75% vs. 48.3%, P = 0.001). Hypertriglyceridemia (58.3% vs. 39.2%, P = 0.01) and metabolic syndrome (23.9% vs. 4.1%, P < 0.001) were significantly more common in CO compared to CNO groups. However, there was no difference in serum high density lipoprotein (HDL), fasting blood glucose, T2 DM, or HTN between CO and CNO groups (Table 1). BMI was also similar between CO [22.08 (21.11–24.49) kg/m2] and CNO [21.95 (20.88–22.54) kg/m2] groups. A poor correlation was observed between BMI and waist circumference (r = 0.24, 95% CI: 0.09–0.38). The scatter diagram of the correlation between waist circumference and BMI in CO and CNO groups is shown in Figure 1.
Table 1.
Demographic and Metabolic Profile of Centrally Obese (CO) and Centrally Nonobese (CNO) Patients With Lean NAFLD (n = 170).
| Characteristic | Centrally obese (CO) lean NAFLD (n = 96) | Centrally nonobese (CNO) lean NAFLD (n = 74) | P value |
|---|---|---|---|
| Male:female | 57:39 | 61:13 | 0.001 |
| Age (years) | 39.2 ± 11.8 | 35.8 ± 11.6 | 0.07 |
| Body mass index (kg/m2) | 22.08 (21.11–24.49) | 21.95 (20.88–22.54) | 0.36 |
| Waist circumference (cm) | 92.5 (89.5–98) | 84.6 (79–87.5) | <0.001 |
| Fasting blood glucose | 94.3 (87.4–105.8) | 93.5 (88–106.6) | 0.61 |
| Type 2 diabetes mellitus | 14 (14.6%) | 11 (14.8%) | 0.95 |
| Hypertension | 9 (9.4%) | 9 (12.2%) | 0.76 |
| Serum triglycerides (mg/dL) | 166 (120.8–222.9) | 146.5 (111.9–178.3) | 0.03 |
| Elevated triglycerides (>150 mg/dL) | 56 (58.3%) | 29 (39.2%) | 0.01 |
| HDL (mg/dL) | 42 (36.8–49.8) | 43.5 (36–49) | 0.65 |
| Decreased HDL | |||
| - Males (<40 mg/dL) | 21 (36.8%) | 19 (31.1%) | 0.24 |
| - Females (<50 mg/dL) | 28 (71.8%) | 11 (84.6%) | 0.36 |
| - Total | 49 (51%) | 30 (27%) | 0.14 |
| Dyslipidemia | 60 (62.5%) | 37 (50%) | 0.10 |
| Metabolic syndrome | 23 (23.9%) | 3 (4.1%) | <0.001 |
HDL, high density lipoprotein; NAFLD, nonalcoholic fatty liver disease.
Figure 1.
Scatter diagram showing correlation of BMI and waist circumference in lean NAFLD patients with or without central obesity (CO). BMI, body mass index; NAFLD, non-alcoholic fatty liver disease.
Noninvasive Assessment of Liver Disease Severity
Abdominal ultrasound parameters and data for calculation of FIB-4 were available in all patients. FibroScan parameters of CAP and LSM were available in 47 (28 CO and 19 CNO) and 104 (63 CO and 41 CNO) patients, respectively.
Transaminase levels were similar between the two groups, as shown in Table 2. Grade of hepatic steatosis on ultrasound assessment was significantly higher in the CO group (P = 0.01, Figure 2). Median CAP was also higher among patients with CO [312.5 (289.8–341) dB/m vs. 275 (268–305.1) dB/m, P = 0.002]. FAST score as a noninvasive measure of NASH with significant fibrosis was also significantly higher in CO patients [0.42 (0.15–0.66) vs. 0.26 (0.11–0.39), P = 0.04]. Compared to CNO, fibrosis assessment using FIB-4 [1.06 (0.65–2.18) vs. 1.03 (0.51–1.71), P = 0.02] and LSM [6.2 (4.8–7.4) kPa vs. 5.7 (4.5–6.6) kPa, P = 0.03] was significantly worse in CO patients (Table 2).
Table 2.
Noninvasive Assessment of Liver Disease Severity in Centrally Obese (CO) and Centrally Nonobese (CNO) Patients With Lean NAFLD (n = 170).
| Characteristic | Centrally obese (CO) lean NAFLD (n = 96) | Centrally nonobese (CNO) lean NAFLD (n = 74) | P value |
|---|---|---|---|
| AST (U/L) | 46 (34.1–76.5) | 49 (33.5–68.3) | 0.54 |
| ALT (U/L) | 68 (44.5–91) | 61.2 (40.3–96.6) | 0.91 |
| Significant elevation in AST (>2X ULN) | 20 (20.8%) | 12 (16.2%) | 0.44 |
| Significant elevation in ALT (>2X ULN) | 33 (34.4%) | 26 (35.1%) | 0.91 |
| Steatosis grade on ultrasound | |||
| -Grade I | 66 (69%) | 65 (87.7%) | |
| -Grade 2 | 18 (19.1%) | 7 (9.2%) | 0.01 |
| -Grade 3 | 12 (11.9%) | 2 (3.1%) | |
| Steatosis assessment using CAP -CAP (dB/m) |
n = 28 312.5 (289.8–341) |
n = 19 275 (258–305.1) |
0.002 |
| FibroScan-AST (FAST) score | n = 28 0.42 (0.15–0.66) |
n = 19 0.26 (0.11–0.39) |
0.04 |
| FIB-4: | 1.06 (0.65–2.18) | 1.03 (0.51–1.71) | 0.02 |
| Liver stiffness measurement (kPa) | n = 63 6.2 (4.8–7.4) |
n = 41 5.7 (4.5–6.6) |
0.03 |
ALT, alanine transaminase; AST, aspartate aminotransferase; CAP, controlled attenuation parameter; LSM, liver stiffness measurement; NAFLD, non-alcoholic fatty liver disease.
Figure 2.
Grade of hepatic steatosis on ultrasound in lean patients with NAFLD (A) or MASLD (B). MASLD, metabolic dysfunction associated steatotic liver disease; NAFLD, non-alcoholic fatty liver disease.
Advanced Fibrosis and Risk Factors
As per FIB-4 cutoff, 25 (14.7%) out of 170 lean patients with NAFLD had evidence of advanced fibrosis. Advanced fibrosis was present in 6 (5.7%) of the 104 patients in whom LSM values were available. Advanced fibrosis was significantly more common in CO group using LSM (P = 0.04) while a trend was observed with FIB-4 (P = 0.09) (Figure 3, Figure 4, Table 3). Since FIB-4 values were available in all patients, it was used for the analysis of risk factors of advanced fibrosis, which was defined as FIB-4 >2.67. CO [aOR: 3.11 (1.10–8.96), P = 0.03] and dyslipidemia [aOR: 3.46 (1.20–9.96), P = 0.02] were associated with increased odds for the presence of advanced fibrosis independent of BMI and the presence of T2 DM or HTN (Table 4).
Figure 3.
Advanced fibrosis as assessed with FIB-4 in lean patients with NAFLD (A) or MASLD (B). MASLD, metabolic dysfunction associated steatotic liver disease; NAFLD, non-alcoholic fatty liver disease.
Figure 4.
Advanced fibrosis as assessed with liver stiffness measurement (LSM) in lean patients with NAFLD (A) or MASLD (B). MASLD, metabolic dysfunction associated steatotic liver disease; NAFLD, non-alcoholic fatty liver disease.
Table 3.
Advanced Fibrosis Using Noninvasive Tests in Centrally Obese (CO) and Centrally Nonobese (CNO) Patients With Lean NAFLD (n = 170).
| Advanced fibrosis | Centrally obese (CO) lean NAFLD | Centrally nonobese (CNO) lean NAFLD | P value |
|---|---|---|---|
| FIB-4 | n = 96 | n = 74 | |
| - Ruled out (FIB-4 <1.3) | 56 (58.4%) | 47 (63.5%) | |
| - Gray-zone (FIB-4 1.3–2.67) | 20 (20.8%) | 22 (29.7%) | 0.09 |
| - Ruled in (FIB-4 >2.67) | 20 (20.8%) | 5 (6.8%) | |
| LSM | n = 63 | n = 41 | |
| - Ruled out (LSM <8 kPa) | 51 (81%) | 38 (92.6%) | |
| - Gray-zone (LSM 8–12 kPa) | 6 (9.5%) | 3 (7.3%) | 0.04 |
| - Ruled in (LSM >12 kPa) | 6 (9.5%) | 0 |
LSM, liver stiffness measurement; NAFLD, non-alcoholic fatty liver disease.
Table 4.
Clinical Predictors of Advanced Fibrosis (FIB-4 >2.67) in Lean NAFLD (n = 170) on Univariate and Multivariate Analysis.
| Risk factor | Advanced fibrosis ruled in (FIB-4 >2.67) [n = 25] | Advanced fibrosis cannot be ruled in (FIB-4 ≤2.67) [n = 145] | P value on univariate analysis | Adjusted odds ratio (95% CI) for ruling in advanced fibrosis (FIB-4 >2.67) on multivariate analysis |
|---|---|---|---|---|
| Central obesity | 20 (80%) | 76 (44.7%) | 0.01 | 3.11 (1.10–8.96), P = 0.03 |
| Body mass index (kg/m2) | 21.85 ± 1.74 | 21.56 ± 1.29 | 0.41 | 1.24 (0.83–1.84), P = 0.29 |
| Diabetes Mellitus | 3 (12%) | 22 (15.2%) | 0.68 | 0.73 (0.19–2.88), P = 0.65 |
| Dyslipidemia | 20 (80%) | 77 (53.1%) | 0.02 | 3.46 (1.20–9.96), P = 0.02 |
| Hypertension | 1 (4%) | 17 (11.7%) | 0.25 | 0.29 (0.04–2.41), P = 0.26 |
MASLD in Lean Patients
There has been much debate about the nomenclature of NAFLD, and a recent Delphi consensus has recommended the terminology of MASLD.27 Hence, we also analyzed our cohort of patients with lean NAFLD according to MASLD criteria. Among 170 lean patients with NAFLD, 142 patients fulfilled the MASLD criteria, among whom 96 (67.6%) patients were CO. The demographic and metabolic profile of CO and CNO lean patients with MASLD are shown in Table 5. Age, BMI, T2DM, HTN, hypertriglyceridemia, and low HDL were comparable among CO and CNO lean MASLD. However, metabolic syndrome was significantly more common in CO-lean MASLD (23.9% vs. 6.5%, P = 0.01).
Table 5.
Metabolic Profile and Noninvasive Assessment of Centrally Obese (CO) and Centrally Nonobese (CNO) Patients With Lean MASLD (n = 142).
| Characteristic | Centrally obese (CO) lean NAFLD (n = 96) | Centrally non-obese (CNO) lean NAFLD (n = 46) | P value |
|---|---|---|---|
| Male:female | 57:39 | 35:11 | 0.05 |
| Age (years) | 39.2 ± 11.8 | 36 ± 11.7 | 0.13 |
| Body mass index (kg/m2) | 22.08 (21.11–24.49) | 22.03 (20.81–23.65) | 0.32 |
| Waist circumference (cm) | 92.5 (89.5–98) | 84.5 (78.2–87) | <0.001 |
| Fasting blood glucose | 94.3 (87.4–105.8) | 91.9 (88–111) | 0.20 |
| Type 2 diabetes mellitus | 14 (14.6%) | 11 (23.9%) | 0.17 |
| Hypertension | 9 (9.4%) | 9 (19.5%) | 0.09 |
| Elevated triglycerides (>150 mg/dL) | 56 (58.3%) | 29 (63%) | 0.59 |
| Decreased HDL | 49 (51%) | 30 (20.5%) | 0.11 |
| Dyslipidemia | 60 (62.5%) | 37 (80.4%) | 0.03 |
| Metabolic syndrome | 23 (23.9%) | 3 (6.5%) | 0.01 |
| AST (U/L) | 46 (34.1–76.5) | 47 (35–69) | 0.35 |
| ALT (U/L) | 68 (44.5–91) | 63 (42–97) | 0.87 |
| Significant elevation in AST (>2X ULN) | 20 (20.8%) | 8 (17.3%) | 0.63 |
| Significant elevation in ALT (>2X ULN) | 33 (34.4%) | 17 (36.9%) | 0.76 |
| Steatosis grade on ultrasound | |||
| -Grade I | 66 (69%) | 40 (87%) | |
| -Grade 2 | 18 (19.1%) | 5 (10.8%) | 0.04 |
| -Grade 3 | 12 (11.9%) | 1 (2.2%) | |
| Steatosis assessment using CAP -CAP (dB/m): |
n = 28 312.5 (289.8–341) |
n = 18 277 (260–305) |
0.001 |
| FibroScan-AST (FAST) score | n = 28 0.42 (0.15–0.66) |
n = 18 0.26 (0.1–0.4) |
0.04 |
| FIB-4: | 1.06 (0.65–2.18) | 1.01 (0.50–1.67) | 0.01 |
| Liver stiffness measurement (kPa) | n = 63 6.2 (4.8–7.4) |
n = 35 5.55 (4.2–6.7) |
0.03 |
ALT, alanine transaminase; AST, aspartate aminotransferase; CAP, controlled attenuation parameter; HDL, high density lipoprotein; LSM, liver stiffness measurement; NAFLD, nonalcoholic fatty liver disease.
Among lean MASLD patients, the grade of hepatic steatosis on ultrasound was significantly worse among those with CO (P = 0.04, Figure 2). Median CAP [312.5 (289.8–341) vs. 277 (260–305), P = 0.001], FAST [0.42 (0.15–0.66) vs. 0.26 (0.1–0.4), P = 0.04], FIB-4 [1.06 (0.65–2.18) vs. 1.01 (0.50–1.67), P = 0.01] and LSM [6.2 (4.8–7.4) vs. 5.55 (4.2–6.7), P = 0.03] were higher in CO MASLD compared to CNO patients (Table 5). Advanced fibrosis was significantly more common among CO lean MASLD on noninvasive assessment using both FIB-4 (P = 0.02) and LSM (P = 0.04) (Figure 3, Figure 4, Table 6). On multivariate analysis, CO [aOR: 3.32 (1.23–8.5), P = 0.02] was independently associated with advanced fibrosis (FIB-4 >2.67) after adjusting for BMI and other metabolic comorbidities (Table 7).
Table 6.
Advanced Fibrosis Using Noninvasive Tests in Centrally Obese (CO) and Centrally Non-obese (CNO) Patients With Lean MASLD (n = 142).
| Advanced fibrosis | Centrally obese (CO) lean NAFLD | Centrally nonobese (CNO) lean NAFLD | P value |
|---|---|---|---|
| FIB-4 | n = 96 | n = 46 | |
| - Ruled out (FIB-4 <1.3) | 56 (58.4%) | 34 (73.9%) | |
| - Gray-zone (FIB-4 1.3–2.67) | 20 (20.8%) | 10 (21.7%) | 0.02 |
| - Ruled in (FIB-4 >2.67) | 20 (20.8%) | 2 (4.3%) | |
| LSM | n = 63 | n = 35 | |
| - Ruled out (LSM <8 kPa) | 51 (81%) | 33 (94.3%) | |
| - Gray-zone (LSM 8–12 kPa) | 6 (9.5%) | 2 (5.7%) | 0.04 |
| - Ruled in (LSM >12 kPa) | 6 (9.5%) | 0 |
LSM, liver stiffness measurement; NAFLD, nonalcoholic fatty liver disease.
Table 7.
Clinical Predictors of Advanced Fibrosis (FIB-4 >2.67) in Lean MASLD (n = 142) on Univariate and Multivariate Analysis.
| Risk factor | Advanced fibrosis ruled in (FIB-4 >2.67) [n = 22] | Advanced fibrosis cannot be ruled in (FIB-4 ≤2.67) [n = 121] | P value on univariate analysis | Adjusted odds ratio (95% CI) for ruling in advanced fibrosis (FIB-4 >2.67) on multivariate analysis |
|---|---|---|---|---|
| Central obesity | 20 (90.9%) | 76 (62.8%) | 0.01 | 3.32 (1.23–8.5), P = 0.02 |
| Body mass index (kg/m2) | 21.9 ± 1.85 | 21.6 ± 1.44 | 0.63 | 1.2 (0.79–1.93), P = 0.47 |
| Diabetes Mellitus | 3 (13.6%) | 22 (18.1%) | 0.60 | 0.88 (0.36–2.17), P = 0.54 |
| Dyslipidemia | 20 (90.9%) | 77 (63.6%) | 0.01 | 3.3 (1.29–8.8), P = 0.02 |
| Hypertension | 1 (4.5%) | 17 (14%) | 0.22 | 0.37 (0.09–2.89), P = 0.66 |
Discussion
Globally lean NAFLD accounts for about 20% of all patients with NAFLD, and Indian studies estimate a pooled prevalence of 16.97%.2,33 While proportionately small, the absolute number of lean individuals with NAFLD is likely to be huge given the gargantuan burden of NAFLD in India. Further, emerging data suggests that lean NAFLD is not innocuous with liver disease severity and long-term outcomes being largely similar to NAFLD in overweight or obese patients.3,18,19 Concerns have been raised whether the change in terminology of NAFLD would underserve these lean patients. We have previously reported that the MASLD definition better captures lean patients with NAFLD as compared to the hitherto proposed metabolic-dysfunction associated fatty liver disease (MAFLD) criteria.34 One of the principal differences between MASLD and MAFLD is the inclusion of CO as a major cardiometabolic risk factor in MASLD, thereby entailing that a lean patient with CO and NAFLD qualifies as MASLD even in the absence of T2DM, HTN, or dyslipidemia. In this study, we found that lean NAFLD patients with CO have more severe noninvasive assessment parameters for steatosis, NASH, and fibrosis compared to their CNO lean counterparts. This observation lends further support to the inclusion of CO as a major cardiometabolic risk factor for categorizing NAFLD as MASLD as per the new criteria.
Clinical risk stratification and screening strategies in lean patients with NAFLD or MASLD remains an unmet need. We observed that lean patients with CO and NAFLD or MASLD have a more than 3 times higher odds of having underlying fibrosis independent of other metabolic risk factors. Advanced fibrosis has been shown to dramatically alter the natural history of NAFLD with an exponential increase in liver-related morbidity and mortality.35 Indeed, several authorities, including EASL and AASLD, incorporate advanced fibrosis as a fundamental part of their risk stratification algorithms.32,36,37 Thus, our data suggests that CO may be used for the initial clinical risk stratification of patients with lean NAFLD or MASLD.
Although our cohort of lean patients was comprised predominantly of males, females were more likely to have underlying CO. Several studies in the general population affirm that females are more likely to have CO than males, particularly in Asian countries. Indeed, a recent urban community-based Indian study that included more than 1100 participants reported two-times higher odds of CO among females.38 Dyslipidemia was significantly more common in patients with CO compared to CNO patients. This is not surprising given the intricate link between an expanded, dysfunctional adipose tissue, insulin resistance, and lipid metabolism. Of note, CO is a better surrogate of visceral adiposity than BMI. Visceral adipose tissue is relatively insulin resistant and inherently prone to lipolysis.39,40 Increased influx of free fatty acids to the liver results in an increased production and efflux of triglycerides from the liver, which accounts for peripheral hypertriglyceridemia. However, this increased efflux of triglycerides from the liver cannot keep pace with their increased production thereby causing an increase in intrahepatic triglycerides.21 Dyslipidemia was also independently associated with advanced fibrosis in both NAFLD and MASLD. Thus, dyslipidemia and CO are intricately linked and appear to be central pathophysiological drivers of NAFLD in lean patients. Intriguingly, T2DM and HTN were associated with neither CO nor advanced fibrosis in our cohort of lean patients. There is no easy explanation for this enigmatic observation, and it may be due to the small number of patients with these comorbidities in our study.
Our study also highlights the inadequacies of BMI as a measure of adiposity and its relevance to risk stratification in lean patients. There was no difference in BMI among CO and CNO patients with NAFLD or MASLD. Further, there was a poor correlation between BMI and waist circumference. Finally, BMI was not associated with advanced fibrosis in NAFLD (aOR: 1.24, 95% CI: 0.83–1.84) or MASLD (1.2 (0.79–1.93), P = 0.47). In light of the perceived inadequacies of BMI as a measure of adiposity, INASL recently suggested incorporating normal weight circumference in addition to normal BMI for defining lean NAFLD.26 Our preliminary data lends credence to such a change as lean patients without central obesity had significantly less severe disease across the full spectrum of NAFLD (MASLD), including steatosis (USG and CAP), NASH (FAST score), and fibrosis (FIB-4 and LSM). However, further multicentric studies are required before such a change in the definition of lean NAFLD or lean MASLD can be recommended in routine parlance.
In our study, CO was ascertained using waist circumference as recommended in the NCEP-ATP III, International Diabetes Federation (IDF) and the European Group for the Study of Insulin Resistance definitions of metabolic syndrome.41, 42, 43 We acknowledge that waist circumference (which also includes abdominal subcutaneous adipose tissue) is an imprecise measure of visceral obesity. Visceral adiposity is more accurately assessed by techniques like dual X-ray energy absorptiometry, computed tomography, magnetic resonance imaging, or positron emission tomography. However, while excellent as research tools, these advanced imaging techniques are not feasible in everyday clinical practice. As such, measuring waist circumference is simple, easy, and requires barely a few minutes. Hence, it can be incorporated as a fundamental part of the clinical evaluation of NAFLD or MASLD by the busy clinician in routine practice. The simplicity of this tool has additional relevance to India, where NAFLD has now been incorporated into the National Programme for Prevention and Control of Non-Communicable Diseases (NP-NCD). Under this program, the initial, primary screening of NAFLD or MASLD at the community level by ASHA workers incorporate waist circumference and not BMI. This has primarily been done for logistical reasons as a measuring-tape is easier to arrange and more portable than a weighing scale in resource-constrained community settings. Our findings lend further support to such an approach as incorporating waist circumference in the initial screening will avoid missing CO-lean patients who remain at a higher risk of having underlying advanced fibrosis.
We acknowledge the limitations of our study. FibroScan parameters were not available in all the patients, and CAP values were available for only those patients who presented after 2015 as CAP was incorporated into FibroScan at our institute in 2015. Waist-hip ratio and waist-height ratio have been suggested as alternatives to waist circumference for defining CO. However, we did not have these data in many of the patients, and it was not included in the analysis. Finally, the inclusion of a non-lean NAFLD group would have added further granularity to our study.
In conclusion, there is poor correlation between BMI and waist circumference in lean patients. Among lean patients with NAFLD or MASLD, those with central obesity have more severe steatosis, at-risk NASH (MASH), and fibrosis on noninvasive assessment with a higher burden of advanced fibrosis compared to those without central obesity.
Credit authorship contribution statement
ArD: conceptualization, patient recruitment, data analysis and manuscript writing; NB: data collection and manuscript writing; MM: data collection and analysis; PS: data collection; SR: patient recruitment, NV: patient recruitment, MP: patient recruitment, ST: patient recruitment and critical revision; AD: conceptualization, patient recruitment, data curation and critical revision.
Funding
None.
Declaration of competing interest
None
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