Lean NAFLD is histologically less severe and tends to affect older patients

doi:10.21203/rs.3.rs-1566257/v1

Objective: Nonalcoholic fatty liver disease (NAFLD) is related to obesity; little is known regarding NAFLD in lean individuals. This study aimed to determine pathological characteristics of lean NAFLD.

Methods: The study enrolled biopsy-proven NAFLD patients from the Third People’s Hospital of Shenzhen from September 2017 to October 2021. Eighty-one patients were enrolled and classified into lean or obese groups by body mass index. Histology severity was assessed according to the steatosis-activity-fibrosis (SAF) score and was compared between lean and obese groups.

Results: Among 81 patients, 12 (14.81%) were lean and 74 (91.36%) had nonalcoholic steatohepatitis (NASH). Lean NAFLD patients had less severe degree of activity (P=0.004) and fibrosis (P =0.047) and a lower proportion of NASH (P<0.001). No differences in steatosis (P=0.215) or advanced fibrosis (P=0.217) were observed. Lean NAFLD (43.83±10.28 vs 36.13±9.85 years, P<0.001) and NASH patients (46.29±12.83 vs 36.12±9.89 years, P=0.014) were older than obese NAFLD/NASH patients. The proportion of lean NAFLD/NASH patients in-creased with age. Compared with obese NAFLD patients, lean NAFLD patients had lower pro-portions of NASH (98.18% vs 42.86%, P<0.001) among patients aged <45 years and less severe fibrosis (P=0.046) among patients aged ≥45 years. No difference in steatosis/activity/fibrosis was observed between the two age groups (<45 years and ≥45 years) among lean NAFLD patients.

Conclusion: In conclusion, fewer severe pathological changes were found in lean NAFLD patients. Histological progress was not significant between lean NAFLD patients aged <45 years and those aged ≥45 years.

lean nonalcoholic fatty liver disease

nonalcoholic steatohepatitis

body mass index

liver histology

age difference

In the past two decades, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased globally, and it has become a major cause of chronic liver diseases (affecting approximately 24–25% of the global population[1–3] and approximately 29–30% of the Chinese population[4, 5]. NAFLD is characterised by the presence of hepatic steatosis affecting more than 5% of hepatocytes not caused by alcoholism, viral hepatitis, steatogenic medications, or lipodystrophy[1, 2]. It includes simple nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma[6, 7].

Although NAFLD usually occurs in individuals with obesity, some people with normal body mass index (BMI) also have NAFLD, termed “lean NAFLD”[8, 9]. Long-term outcomes of lean NAFLD vary in different studies[10–13]. The severity of steatohepatitis and fibrosis are the two main prognostic factors, of which the degree of fibrosis is the most important factor[14, 15]. Accumulating evidence suggests that the liver pathophysiology of lean NAFLD differs from that of non-lean NAFLD, which may explain the different outcomes. Studies from international[16], Australia and Italy[17], Turkey[18], India[19] and Hong Kong China[20] report that lean patients tend to have less severe hepatic fibrosis with or without less hepatic inflammation. In contrast, two different studies from Australia[13, 21] reported that lean NAFLD progressed more histologically than overweight NAFLD and was associated with increased liver-related mortality. Patients with lean NAFLD were reported to be older[20, 22], younger[16], or similar[17] in age than those with obese NAFLD in different studies. These conflicting results from different regions suggest that more pathological data of lean NAFLD are needed. To date, little is known about the pathological features of lean NAFLD in mainland China.

Therefore, to determine the characteristics of lean NAFLD in southern China, this study aimed to retrospectively classify biopsy-proven NAFLD based on BMI and compare their histologic severity.

Study population

This was a single-centre, retrospective, cross-sectional study enrolling patients who underwent liver biopsies at the Third People’s Hospital of Shenzhen, China from September 2017 to October 2021 and met the diagnostic criteria for NAFLD. The diagnosis of NAFLD was based on the presence of > 5% hepatic steatosis in the absence of alcoholic liver disease, viral hepatitis, steatogenic medications, autoimmune disease, Wilson’s disease, other inherited or metabolic liver diseases, hepatocellular carcinoma, or liver transplantation status. BMI was calculated using weight (kg)/[height (m)]². Lean individuals were those with BMI < 24 kg/m² and obese individuals were defined as having BMI ≥ 24 kg/m². A total of 81 patients with biopsy-proven NAFLD were enrolled in this study, including 66 male and 15 female. The study was conducted in accordance with the Declaration of Helsinki, and was approved by the Ethics Committee of Shenzhen Third People’s Hospital (No. 2021-018).

Data collection

Data regarding the following factors were collected from electronic medical records at the time of biopsy: age, sex, BMI, history of type 2 diabetes mellitus (T2DM), systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profile, haemoglobin A1c, fasting blood sugar, uric acid (UA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, albumin, alkaline phosphatase, total bile acid, and ferritin levels.

Histologic assessment

Liver histology was reassessed by two experienced pathologists according to the steatosis-activity-fibrosis (SAF) score, which comprised steatosis (S, stages 0–3), lobular inflammation (LI, stages 0–2) and ballooning (B, stages 0–2), and fibrosis (F, stages 0–4). Activity (A) is the combined score for LI and ballooning. If S ≥ 1 and A ≥ 2 (at least one point from LI and one point from ballooning) were observed, a diagnosis of NASH was established. Advanced fibrosis was diagnosed when the fibrosis score was 3 or 4.

Statistical analyses

Statistical analyses were conducted using SPSS Statistics version 22.0 (IBM, Armonk, NY). Continuous variables are presented as mean ± standard deviation and compared using Student’s t-test. Categorical variables were compared using the χ² test, and ordinal variables were compared using the linear-by-linear association test (P for trend). Statistical significance was set at p values < 0.05.

Clinical characteristics of lean and obese NAFLD

Eighty-one biopsy-proven NAFLD patients were enrolled in this study. Patient characteristics are shown in Table 1. The average age was 37.27 ± 10.23 years, and the mean BMI was 27.08 ± 3.57 kg/m². Among the participants, 66 (81.48%) were male, 18 (22.22%) had T2DM, 31 (38.27%) had SBP ≥ 130 mmHg, and 25 (30.86%) had DBP ≥ 85 mmHg.

The lean and obese groups included 12 (14.81%) and 69 (85.19%) patients, respectively. In the lean participants, significant difference was found in age, SBP, HDL, UA and ALT in comparison to obese. Lean participants were older (43.83 ± 10.28 vs 36.13 ± 9.85 years, P < 0.001) and had a lower proportion of SBP ≥ 130 mmHg (8.33% vs 43.48%, P = 0.022) than obese participants. Higher HDL-c (1.12 ± 0.3 vs 1.06 ± 0.26 mmol/L, P = 0.047) and lower UA (353 ± 76.89 vs 442.93 ± 118.67 µmol/L, P < 0.001) and ALT (53.8 ± 50.93 vs 116.67 ± 85.12 U/L, P < 0.001) levels were observed in lean NAFLD patients than in obese NAFLD patients. No significant differences were observed with respect to sex, T2DM, or DBP.

Table 1

Clinical characteristics of the population with biopsy-proven NAFLD
Variable	lean (n = 12)	obese (n = 69)	total(n = 81)	P value
age(year)	43.83 ± 10.28	36.13 ± 9.85	37.27 ± 10.23	< 0.001
male n(%)	8(66.67)	58(87.88)	66(81.48%)	0.304
BMI(kg/m2)	22.77 ± 0.71	27.84 ± 3.33	27.08 ± 3.57	0.006
T2DM n(%)	2(16.57)	16(23.19)	18(22.22)	0.618
SBP > = 130mmHg n(%)	1(8.33)	30(43.48)	31(38.27)	0.022
DBP > = 85mmHg n(%)	2(16.67)	23(33.33)	25(30.86)	0.252
HDL-c(mmol/L)	1.12 ± 0.3	1.06 ± 0.26	1.07 ± 0.26	0.047
LDL-c(mmol/L)	3.37 ± 1.18	3.19 ± 0.88	3.22 ± 0.93	0.341
CHO(mmol/L)	5.31 ± 1.42	4.9 ± 1.01	4.96 ± 1.08	0.097
TG(mmol/L)	2.43 ± 2.48	2.21 ± 1.84	2.24 ± 1.93	0.876
HbA1c(%)	6.02 ± 0.7	6.29 ± 0.89	6.26 ± 0.87	0.435
FBG(mmol/L)	5.17 ± 0.69	5.19 ± 0.88	5.19 ± 0.85	0.143
HOMA-IR	3.45 ± 0.25	3.31 ± 0.70	3.34 ± 0.64	0.669
UA(umol/L)	353 ± 76.89	442.93 ± 118.67	429.6 ± 117.55	< 0.001
ALT(U/L)	53.8 ± 50.93	116.67 ± 85.12	107.36 ± 83.78	< 0.001
ALT > = 40U/L	5(41.67)	62(89.86)	67(82.72%)	< 0.001
AST(U/L)	33.91 ± 28.2	58.71 ± 57.66	55.03 ± 54.09	0.291
AST > = 40U/L	3(25.00)	41(59.42)	44(54.32)	0.028
TB(umol/L)	12.38 ± 4.34	15.78 ± 10.72	15.27 ± 10.09	0.979
ALB(g/L)	45.96 ± 3.23	45.78 ± 3.09	45.81 ± 3.09	0.102
ALP(U/L)	71.64 ± 18.76	79.86 ± 25.53	78.73 ± 10.23	0.935
GGT(U/L)	89.8 ± 133.72	86.39 ± 56.54	86.90 ± 71.95	0.969
TBA(umol/L)	3.73 ± 2.17	5.36 ± 5.37	5.12 ± 5.05	0.744
Ferritin(ng/mL)	497.14 ± 439.11	629.68 ± 413.17	612.24 ± 416.08	0.766

SBP: systolic blood pressure, DBP: diastolic blood pressure, T2DM: type 2 diabetes mellitus, HDL-c: high-density lipoprotein cholesterol, LDL-c: low-density lipoprotein cholesterol, CHO: cholesterol, TG: triglycerides, FBG: fasting blood glucose, UA: uric acid, ALT: alanine aminotransferase, AST: aspartate transaminase, ALB: albumin, ALP: Alkaline phosphatase, GGT: γ-glutamyltranspeptidase, TBA: total bile acids.

Comparison of histologic features between lean and obese NAFLD

The distributions of steatosis, activity, and fibrosis are shown in Table 2. There were 74 (91.36%) patients with NASH and eight (9.88%) with advanced fibrosis. Although no difference in steatosis was observed between the lean NAFLD and obese NAFLD groups (P = 0.215), a higher proportion of activity score (P = 0.004) and fibrosis score (P = 0.047) was more common in the obese NAFLD group than in the lean NAFLD group.

Table 2

Comparison of histologic features between lean and obese NAFLD.
Variable	lean (n = 12)	obese (n = 69)	total(n = 81)	P
Steatosis				0.215
5–33%	7(58.33)	1(33.33)	30(37.04)
> 33–66%	3(25.00)	32(46.38)	35(43.21)
> 66%	2(16.67)	14(20.29)	16(19.75)
Activity				0.004
0	1(8.33)	0(0.00)	1(1.23)
1	4(33.33)	2(2.90)	6(7.41)
2	4(33.33)	39(56.52)	43(53.09)
3	3(25.00)	19(27.54)	43(27.16)
4	0(0.00)	9(13.04)	9(11.11)
Fibrosis				0.047
0	4(33.33)	11(15.94)	15(18.52)
1	6(50.00)	28(40.58)	24(41.98)
2	2(16.67)	22(31.88)	24(29.63)
3	0(0.00)	7(10.14)	7(8.64)
4	0(0.00)	1(1.45)	1(1.23)
NASH	7(58.33)	67(97.1)	74(91.36)	< 0.001
advanced fibrosis	0(0.00)	8(11.59)	8(9.88)	0.217

Clinical characteristics of the population with biopsy-proven NASH

There were 74 patients defined as having NASH according to the SAF score; they had an average age of 37.08 ± 10.53 years and mean BMI of 27.32 ± 3.52 kg/m², and 82.43% of the NASH patients were male. Patients in the lean NASH group were older (46.29 ± 12.83 vs 36.12 ± 9.89, P = 0.014) and had a lower proportion of evaluated DBP (0.00% vs 32.84%, P = 0.002) and lower levels of UA (335.14 ± 80.08 vs 444.51 ± 120.06 µmol/L, P = 0.022) than patients in the obese NASH group. No differences in sex, T2DM, lipid profile, or liver function profile were found between the lean and obese NASH groups.

3.4 Distribution trend with age in NAFLD or NASH

Age differences were observed in lean NAFLD and lean NASH groups; therefore, we divided patients into three groups according to age (18 to 34 years, 35 to 44 years, and ≥ 45 years). The occurrence of lean NAFLD (Fig. 1A, P = 0.014) and NASH (Fig. 1B, P = 0.025) increased with age.

Table 3

Clinical characteristics of the population with biopsy-proven NASH
Variable	lean (n = 7)	obese (n = 67)	total(n = 74)	P
age(year)	46.29 ± 12.83	36.12 ± 9.89	37.08 ± 10.53	0.014
male n(%)	4(57.14)	57(85.07)	61(82.43)	0.099
BMI(kg/m2)	22.50 ± 0.72	27.83 ± 3.31	27.32 ± 3.52	< 0.001
T2DM n(%)	2(28.57)	16(23.88)	18(24.32)	0.785
SBP > = 130mmHg	1(14.29)	29(43.28)	30(40.54)	0.14
DBP > = 85(mmHg)	0(0.00)	22(32.84)	22(29.73)	0.022
HDL-c(mmol/L)	1.05 ± 0.24	1.06 ± 0.26	1.06 ± 0.25	0.894
LDL-c(mmol/L)	3.36 ± 1.45	3.21 ± 0.88	3.22 ± 0.93	0.693
CHO(mmol/L)	5.26 ± 1.6	4.92 ± 1.00	4.95 ± 1.06	0.427
TG(mmol/L)	2.94 ± 3.23	2.2 ± 1.86	2.27 ± 2.01	0.354
HbA1c(%)	6.18 ± 0.84	6.30 ± 0.90	6.29 ± 0.88	0.79
FBG(mmol/L)	5.1 ± 0.54	5.19 ± 0.89	5.18 ± 0.86	0.806
HOMA-IR	3.30 ± 0.12	3.31 ± 0.7	3.31 ± 0.65	0.72
UA(umol/L)	335.14 ± 80.08	444.51 ± 120.06	434.17 ± 120.82	0.022
ALT(U/L)	60.8 ± 57.35	119.12 ± 85.17	113.61 ± 84.40	0.082
AST(U/L)	39.56 ± 33.47	59.85 ± 58.13	57.93 ± 56.42	0.369
TB(umol/L)	11.11 ± 3.94	15.88 ± 10.85	15.43 ± 10.48	0.255
ALB(g/L)	45.04 ± 2.61	45.83 ± 3.11	45.76 ± 3.06	0.521
ALP(U/L)	62.5 ± 15.11	80.52 ± 25.31	79.04 ± 25.06	0.092
GGT(U/L)	60.23 ± 45.67	85.06 ± 54.6	82.71 ± 54.04	0.25
TBA(umol/L)	3.50 ± 2.34	5.42 ± 5.43	5.24 ± 5.24	0.36
Ferritin(ng/mL)	415.17 ± 250.69	642.97 ± 411.54	623.45 ± 404.13	0.189

Histologic features between lean and obese NAFLD according to the age subgroup

The patients were divided into two subgroups according to their age. Among 62 NAFLD patients aged < 45 years, seven (11.29%) were lean and 55 (88.71%) had obesity. Lean NAFLD patients had less activity (P = 0.01), and NASH was less common (42.86% vs. 98.18%, P < 0.001). Advanced fibrosis was not observed in the lean group. However, no significant difference in fibrosis levels was found between two groups. (Table 4.)

Among 19 NAFLD patients aged ≥ 45 years, there were five (26.32%) lean individuals and 14 (73.68%) individuals with obesity. The obese group had a more severe fibrosis stage (P = 0.046) but showed no difference in steatosis or activity. (Table 4.)

Table 4

Comparison of histologic features between lean and obese NAFLD in age subgroup
Variable	age < 45				age > = 45
Variable	lean (n = 7)	obese (n = 55)	total (n = 62)	P	lean (n = 5)	obese (n = 14)	total (n = 19)	P
Steatosis				0.631				0.198
5–33%	4(57.14)	18(32.73)	22(35.48)		3(60.00)	5(35.71)	8(42.11)
> 33–66%	1(14.29)	27(49.09)	28(45.16)		2(40.00)	5(35.71)	7(36.84)
> 66%	2(28.57)	10(18.18)	12(19.35)		0(0.00)	4(28.57)	4(21.05)
Activity				0.01				0.244
0	0(0.00)	0(0.00)	0(0.00)		1(20.00)	0(0.00)	1(5.26)
1	4(57.14)	1(1.82)	5(8.06)		0(0.00)	1(7.14)	1(5.26)
2	1(14.29)	30(54.55)	31(50.00)		3(60.00)	9(64.29)	12(63.16)
3	2(28.57)	17(30.91)	19(30.65)		1(20.00)	2(14.29)	3(15.79)
4	0(0.00)	7(12.73)	7(11.29)		0(0.00)	2(14.29)	2(10.53)
Fibrosis				0.22				0.046
0	2(28.57)	1(18.18)	12(19.35)		2(40.00)	1(7.14)	3(15.79)
1	4(57.14)	24(43.64)	28(45.16)		2(40.00)	4(28.57)	6(31.58)
2	1(14.29)	17(30.91)	18(29.03)		1(20.00)	5(35.71)	6(31.58)
3	0(0.00)	3(5.45)	3(4.84)		0(0.00)	4(28.57)	4(21.05)
4	0(0.00)	1(1.82)	1(1.61)		0(0.00)	0(0.00)	0(0.00)
NASH	3(42.86)	54(98.18)	57(91.94)	< 0.001	4(80.00)	13(92.86)	17(89.47)	0.447
advanced fibrosis	0	4(7.27)	4(6.45)	0.464	0(0.00)	4(28.57)	4(21.05)	0.094

Histologic features between different ages in lean or obese NAFLD

In the lean NAFLD group, no significant difference in steatosis, activity, or fibrosis was found between younger (< 45 years) and older (≥ 45 years) patients. In the obese NAFLD group, patients aged ≥ 45 years had similar steatosis and activity but a more severe fibrosis stage than patients aged < 45 years. (Table 5.)

Table 5

Comparison of histologic features between different age in lean or overweight NAFLD.
Variable	lean				obese
Variable	age < 45 (n = 7)	age > = 45 (n = 5)	Total (n = 12)	P	age < 45 (n = 55)	age > = 45 (n = 14)	Total (n = 69)	P
Steatosis				0.498				0.799
5–33%	4(57.14)	3(60.00)	7(58.33)		18(32.73)	5(35.71)	23(33.33)
> 33–66%	1(14.29)	2(40.00)	3(25.00)		27(49.09)	5(35.71)	32(46.38)
> 66%	2(28.57)	0(0.00)	2(16.67)		10(18.18)	4(28.57)	14(20.29)
Activity				0.897				0.408
0	0(0.00)	1(20.00)	1(8.33)		0(0.00)	0(0.00)	0(0.00)
1	4(57.14)	0(0.00)	4(33.33)		1(1.82)	1(7.14)	2(2.90)
2	1(14.29)	3(60.00)	4(33.33)		30(54.55)	9(64.29)	39(56.52)
3	2(28.57)	1(20.00)	3(25.00)		17(30.91)	2(14.29)	19(27.54)
4	0(0.00)	0(0.00)	0(0.00)		7(12.73)	2(14.29)	9(13.04)
Fibrosis				0.892				0.042
0	2(28.57)	2(40.00)	4(33.33)		10(18.18)	1(7.14)	11(15.94)
1	4(57.14)	2(40.00)	6(50.00)		24(43.64)	4(28.57)	28(40.58)
2	1(14.29)	1(20.00)	2(16.67)		17(30.91)	5(35.71)	22(31.88)
3	0(0.00)	0(0.00)	0(0.00)		3(5.45)	4(28.57)	7(10.14)
4	0(0.00)	0(0.00)	0(0.00)		1(1.82)	0(0.00)	1(1.45)
NASH	3(42.86)	4(80.00)	7(58.33)	0.218	54(98.18)	13(92.86)	67(97.1)	0.293
advanced fibrosis	0(0.00)	0(0.00)	0(0.00)	1	4(7.27)	4(28.57)	8(11.59)	0.027

In this study, we retrospectively assessed the histological severity of NAFLD in lean and obese patients. In summary, lean NAFLD occurred in approximately 14.81% (n = 12) of the total patients. Lean NAFLD/NASH patients were older age and had a less severe degree of activity and fibrosis and therefore a lower proportion of NASH but no difference in advanced fibrosis (Tables 1–3). Furthermore, the proportion of lean NAFLD/NASH increased with increasing age (Fig. 1). Compared with obese NAFLD, lean NAFLD was accounted with less severe activity (LI and ballooning) in patients aged < 45 years and less severe fibrosis in those aged ≥ 45 years (Table 4). However, no difference in steatosis/activity/fibrosis was observed between different age groups (< 45 years and ≥ 45 years) in lean NAFLD patients, whereas obese NAFLD patients tended to have severe fibrosis (Table 5).

The prevalence of lean NAFLD in the NAFLD population differs among different regions. The proportion of lean NAFLD were 51.3% in Europe, 37.8% in Eastern Asia, 12.9% in Southeast Asia, and 44.3% in mainland China[9]. In our study, lean NAFLD accounted for 14.81% of NAFLD cases, which was lower than that reported in a previous study[9]. Ultrasound was commonly used to diagnose NAFLD and evaluate the prevalence of non-obesity in previous studies, and it may misdiagnose mild NAFLD. In this study, we used liver biopsy as the diagnostic method, and patients selected for liver biopsy are more likely to have elevated enzyme levels. The diagnostic sensitivity and selection bias may partially explain the different prevalence of lean NAFLD observed in China.

In our study, the proportions of NASH were 58.33% and 97.10% in lean and obese NAFLD patients, respectively, which was higher than that reported in previous studies. NASH was observed in 43.5% and 51.9% of lean and obese NAFLD cases, respectively, in Hong Kong China[20], 28%, 47%, and 38% of lean, overweight, and obese NAFLD cases, respectively, in India[19], and 54.1% and 71.2% of lean and obese NAFLD cases, respectively, among Caucasians[16]. The high prevalence of NASH in our study may be due to a large proportion of patients who underwent biopsy had elevated ALT/AST levels: 82.72% (n = 67) with ALT ≥ 40 U/L and 54.32% (n = 44) with AST ≥ 40 U/L. On the other hand, many studies have defined lean and overweight/obesity according to BMI. But some studies have found that central obesity may pose a greater threat than general obesity[23], and waist circumstance is a simple and accessible index to diagnose NAFLD[24]. It is common for Asians to have normal BMI and increased abdominal adiposity[25]. Although waist circumference was not recorded in our study, increased abdominal adiposity in Asians have led to a high prevalence of NASH.

We found that the age difference was significantly higher in the lean NAFLD/NASH groups. This was consistent with findings of a recent meta-analysis that involved 7752 Japanese NAFLD patients[22] and a retrospective study from the US[26]. However, in these two studies, lean NAFLD was reported to have higher all-cause mortality. Liver fibrosis drives the progress of NAFLD[27]. Increased mortality of lean NAFLD patients as reported in different studies suggests that lean NAFLD may have more serious pathological progression. However, a few published histological studies on NAFLD have reported conflicting conclusions. Two studies from Australia by Feldman et al.[13] and Denkmayr et al.[21] reported that pathological changes were more severe in lean NAFLD, while Kumar et al.[19], Younes et al.[16], Chen et al.[17], and Leung et al.[20] reported the opposite. Interestingly, some patients in the study by Younes et al. and all patients in the study by Chen et al. were from Australia. In our study, lean patients with NAFLD had less severe hepatic inflammation and fibrosis. There was no difference in histology in older patients with lean NAFLD, but more severe fibrosis was observed in older patients with obese NAFLD. This phenomenon indicated that the progression of lean NAFLD was slower than that of obese NAFLD. The reasons why pathological changes differ in lean NAFLD patients are unclear. This may be related to environmental or genetic factors. Patients with lean NAFLD have been reported to have a distinct gut macrobiotic profile[17, 28], which may be because of different dietary habits and environments. Patatin-like phospholipase domain-containing protein (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genetic polymorphisms are the best-effective determinants of NASH and severe fibrosis[29]. The PNPLA3 (G) allele was reported to have a higher prevalence in lean individuals according to some studies[30, 31], and it had a greater effect on Asian lean individuals than overweight individuals[32]. The TM6SF2 variant (decreased expression of TM6SF2) increases triglyceride levels[33] and therefore increases the risk of NAFLD and NASH. These environmental and genetic differences may partly explain the contradictory results of different studies.

Our study provided histological data regarding lean NAFLD in mainland China where such histological information was limited. This study had some limitations. First, this was a retrospective cross-sectional study conducted at a single centre with a small population. Second, although we enrolled all biopsy-proven cases within a specific period, selection bias was inevitable. The major reason for liver biopsy was the elevated transaminase levels. Third, no long-term outcomes were observed in these patients.

Lean NAFLD accounted for 14.81% of the NAFLD population. Lean NAFLD/NASH patients were older and had less severe histological activity and fibrosis. Although the proportion of lean NAFLD patients increased with age, significant histological progress was not observed. Larger, prospective, multicentre cohort studies are needed to further elucidate different aspects of lean NAFLD.

NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; BMI: body mass index; SBP: systolic blood pressure, DBP: diastolic blood pressure, T2DM: type 2 diabetes mellitus, HDL-c: high-density lipoprotein cholesterol, LDL-c: low-density lipoprotein cholesterol, CHO: cholesterol, TG: triglycerides, FBG: fasting blood glucose, UA: uric acid, ALT: alanine aminotransferase, AST: aspartate transaminase, ALB: albumin, ALP: Alkaline phosphatase, GGT: γ-glutamyltranspeptidase, TBA: total bile acids.

Acknowledgements

Not applicable.

Author Contributions

Conceptualization, X.W. and F.W.; methodology, Q.T.; software, X.Z.; validation, X.Z. and Z.L.; formal analysis, Q.T., X.Z. and C.L.; data curation, R.C. and W.X.; writing—original draft preparation, X.W. and Q.T; writing—review and editing, X.W. and X.Z.; visualization, Z.L. and C.L.; supervision, G.Z. and F.W.; project administration, G.Z. and F.W.; funding acquisition, Q.T. and F.W. All authors have read and agreed to the published version of the manuscript.

Funding

This work is supported by Shenzhen Key Medical Discipline Construction Fund (No. SZXK076).

Availability of data

The data analysed in the current study belongs to the Third People’s Hospital of Shenzhen. They are not publicly available but are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the Third People’s Hospital of Shenzhen (No. 2021-018). The data was obtained from the past electronic medical records, and the Ethics Committee agreed the application that informed consent was not required.

Consent for publication

Not available.

Conflicts of Interest

The authors declare no conflicts of interest.

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No competing interests reported.

Lean NAFLD is histologically less severe and tends to affect older patients

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Study population

Data collection

Histologic assessment

Statistical analyses

Results

Clinical characteristics of lean and obese NAFLD

Comparison of histologic features between lean and obese NAFLD

Clinical characteristics of the population with biopsy-proven NASH

3.4 Distribution trend with age in NAFLD or NASH

Histologic features between lean and obese NAFLD according to the age subgroup

Histologic features between different ages in lean or obese NAFLD

Discussion

Conclusions

Abbreviations

Declarations

References

Competing Interests

Status:

Version 1