Clinical features of metabolism-related fatty liver disease in the non-lean population

doi:10.21203/rs.3.rs-2009818/v1

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Clinical features of metabolism-related fatty liver disease in the non-lean population

https://doi.org/10.21203/rs.3.rs-2009818/v1

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Objective

To assess the clinical and histological features of metabolic associated fatty liver disease (MAFLD) in non-lean population.

Methods

Current study enrolled consecutive non-lean (Body Mass Index (BMI) > 23 kg/m²) patients with MAFLD and available liver biopsy results. Patients were stratified by BMI into two groups for the comparison of their clinical and histological variables, which included the overweight (BMI 23 ~ < 28 kg/m2) and the obese (BMI ≥ 28 kg/m2). Risk factors for moderate to severe fibrosis (stage > 1) were also analysed through the logistic regression model.

Results

Among 184 non-lean patients with MALFD enrolled, 65 and 119 were overweight and obese, respectively. Patients in the obesity group had a significantly lower level of gamma-Glutamyl transpeptidase (GGT), higher levels of platelet (PLT), Glucose (Glu), prothrombin time (PT), and more common of moderate to severe inflammatory activity when compared to those in the overweight group. However, a significant low frequency of moderate to severe fibrosis was found in the obesity group vs the overweight group (19.33% vs 40.00%, P = 0.002). Multivariate logistic regression analysis of fibrosis found that aspartate transaminase (AST), BMI, alanine transaminase (ALT) and cholesterol (CHOL) were independent predictors for moderate to severe fibrosis in non-lean patients with MAFLD. Compared with the traditional FIB-4 (AUC = 0.77) and APRI (AUC = 0.79) indexes, the combined index based on AST, BMI, ALT and CHOL was more accurated in predicting moderate to severe fibrosis in non-lean patients with MAFLD (AUC = 0.87).

Conclusions

Clinical and histological features differed between obesity and overweight patients with MAFLD. When compared to the traditional serum markers, the combination index including AST, BMI, ALT and CHOL provides a better model to predictor moderate to severe fibrosis in non-lean patients with MAFLD.

metabolic associated fatty liver disease

overweight

obese

fibrosis

With urbanization, modernization and westernization of dietary structure, non-alcoholic fatty liver disease (NAFLD) has become the world's largest chronic liver disease ^[1]. NAFLD is the manifestation of metabolic syndrome (MetS) in the liver, and the latest international consensus recommends that it be renamed as Metabolic associated fatty liver disease (MAFLD). According to the guidelines for the diagnosis and treatment of MAFLD issued by the Asia-Pacific Society of Hepatology in 2020^[2], regardless of the presence or absence of metabolic syndrome, overweight and obese patients diagnosed with fatty liver by abdominal ultrasonography or liver biopsy pathology or other imaging methods can be clearly diagnosed MAFLD. Body Mass Index (BMI) is closely related to the occurrence and development of MAFLD. With the increase of BMI, the prevalence of MAFLD increases significantly, and increased BMI is a risk factor for MAFLD^[3,4].

Increased BMI is not only a risk factor for MAFLD but also determine severity of MAFLD. Lean MAFLD patients have lower prevalence of insulin resistance and less hepatic fibrosis compared to non-lean (overweight/obese) MAFLD ^[5,6]. And data on clinical characteristics, metabolic profiles, and histopathological severity in non-lean patients have yet to be fully explored. Recent study analysis the clinical features between overweight and obese MAFLD, which shown BMI was associated with hepatic steatosis and fibrosis ^[7]. The above results hinted that weight control can improve MAFLD patient outcome, while most of these patients were not underwent with liver biopsy. Furthermore, validation of conventional non-invasive fibrosis scoring systems in MAFLD patients shown that aspartate aminotransferase to platelet ratio index (APRI) scores do not perform well in MAFLD, a new threshold of fibrosis-4 index (FIB-4) was needed, so novel non-invasive scoring systems for fibrosis are required for MAFLD^[8]. With that in mind, we designed a cross-sectional study to compare the clinical presentation and pathological findings between overweight and obese patients with MAFLD. In addition, the study except to develop, validate and compare a non-invasive scoring system for moderate to severe fibrosis in non-lean MAFLD patients.

1) Study population Patients who were pathologically diagnosed with MAFLD by liver biopsy from April 1, 2017 to May 31, 2022 in the Fifth Hospital of Shijiazhuang and the First Affiliated Hospital of Jinan University were selected. This study was approved by the Medical Ethics Committee of The Fifth Hospital of Shijiazhuang (approval number: LL2016003) and the Medical Ethics Committee of The First Affiliated Hospital of Jinan University (approval number: KY-2022-048)

Inclusion criteria: (1) Liver biopsy histology showed fatty liver; (2) BMI>23 kg/m² with or without type 2 diabetes or metabolic dysfunction. Exclusion criteria: (1) patients with other viral liver diseases (hepatitis A, C, E) or HIV infection; (2) patients with alcoholic liver disease, autoimmune liver disease, drug-induced liver injury, hepatolenticular degeneration, total parenteral nutrition and toxic liver disease, etc.; (3) patients with liver cancer and other malignant tumors; (4) combined with other autoimmune diseases.

2) Data assessment and collection All study objectives underwent medical history collection and clinical check-up. A medical history of alcohol consumption, and details of personal medicine prescriptions, hypertension, diabetes, viral hepatitis and autoimmune hepatitis were collected before a general examination.

Patients’ body mass and height were assessed, and the BMI (kg/m²) was calculated as body mass divided by height squared. Blood pressure was also assessed, and hypertension was defined as a systolic blood pressure of ≥140 mmHg and/or a diastolic blood pressure of 90 mmHg, a self-reported history of hypertension, and/or the use of antihypertensive drugs. Diabetes was defined as having fasting plasma Glucose≥7.0mmol/L, a self-reported history of diabetes, and/or undergoing treatment of oral antidiabetic agents. Fasting venous blood samples were obtained within seven days before the biopsy, and used for measurements of the following parameters by conventional laboratory techniques: the complete blood cell counts, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-Glutamyl transpeptidase (GGT), total bilirubin (TB), direct bilirubin (DB), total protein, albumin(ALB), globulin (GLB), prealbumin (PA), cholinesterase (CHE), blood Glucose (Glu), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglycerides (TG), uric acid (UA), urea, creatinine, and prothrombin time (PT).

FibroScan was measured 1～30 days before liver biopsy. FibroScan was used for the measure of liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) via transient elastography by trained operators in accordance with the manufacturer’s instruction. Standard M probe was used in the first instance so that both LSM and CAP could be obtained. The XL probe was used in obese patients when the M probe failed. Ten successful acquisitions were performed in each patient. LSM and CAP values are expressed as the median of all valid measurements obtained.

3) Histological data

Morbid obsess patients underwent intro-operative liver biopsies during bariatric surgery, while other patients undergoing liver puncture. The samples were fixed in formalin and embedded in paraffin, sections were cut and prepared by haematoxylin-eosin staining for morphological evaluation, Masson’s trichrome staining, and reticulin staining for fibrosis assessment. All MAFLD sections were scored by two liver pathologists using FLIP-SAF, who were blind to the study protocol and the pathology report should include the presence and extent of hepatocyte steatosis, ballooning, intralobular inflammation, and liver fibrosis ^[9]. MAFLD was pathologically diagnosed if the steatosis area was > 5%. Hepatic steatosis was assigned on a scale of 0 to 3 (S0: <5%; S1: 5%-33%, S2: 34%-66%, S3: >67%), ballooning of hepatocytes and lobular inflammation was graded from 0 to 2 and fibrosis was assigned a score of 0, 1, 2, 3, or 4 (stage 0, no fibrosis; stage 1, perisinusoidal or periportal fibrosis; stage 2, perisinusoidal and portal/periportal fibrosis; stage 3, bridging fibrosis; and stage 4, cirrhosis). The grade of activity (from A0 to A4) was calculated by addition of grades of hepatocytes ballooning and lobular inflammation. “Moderate to severity activity/ fibrosis” was defined as activity/fibrosis score of more than 2.

4) Statistical Methods

SPSS 24.0 statistical software was applied, measurement data conforming to normal distribution were expressed as x±s, and t test was used for comparison between groups; The measurement data that do not conform to the normal distribution are represented by the median M (P25, P75), and the rank sum test is used for comparison between groups; Enumeration data were expressed as the number of cases (percentage), and the comparison between groups was performed by c2 test. Multivariate logistic regression analysis was performed on the relevant factors with statistical significance at the test level of 0.05 in univariate analysis. Logistic regression analysis used the likelihood ratio advance method to screen variables, and the test level of the introduced variables was α=0.10. And the independent factors affecting the occurrence of the disease were analyzed by the multivariate adjusted OR value. The diagnostic efficacy was analyzed by receiver operating characteristic (ROC) curve. P<0.05 was considered to be statistically significant.

1. Clinical features of overweight and obese MAFLD

Because of the obvious positive correlation between age and liver fibrosis, age adjustment was performed for the two groups of MAFLD patients. According to the above inclusion, exclusion criteria and age adjustment, 184 non-lean MAFLD patients were finally included, including 65 overweight (BMI 23~<28 kg/m²) and 119 obese (BMI≥28 kg/m²) MAFLD patients. Out of 184 non-lean MAFLD subjects, 80 were male, 104 were female. The median age was 36 years old. 28.8% non-lean MAFLD patients had diabetes or abnormal blood sugar, and 25.0% had hypertension. A small number non-lean MAFLD patients (9.8%) were with drinking history. There were more women in obese group than overweight group. There was no significantly difference between the two subgroups on the other mentioned items (Table 1).

The levels of WBC and PLT in peripheral blood of obese MAFLD group were significantly higher than those of overweight MAFLD group, the difference was statistically significant, P<0.05. The levels of ALT, AST and GGT in the two groups were all higher than the upper limit of normal values, and the levels of ALT, AST and GGT in the overweight MAFLD group were significantly higher than those in the obese MAFLD group (P<0.05). The levels of TB, DB and ALB in the overweight MAFLD group were significantly higher than those in the obese MAFLD group, while the GLB and PT levels were lower, the differences were statistically significant (P<0.05), but they were all within the normal range. The levels of UA and Glu in the two groups were higher than normal levels, and the levels of UA and Glu in the obese MAFLD group were higher than those in the overweight MAFLD group (P<0.05). However, there were no statistical significance in blood lipid, renal function and other indicators (P> 0.05), as shown in Table 2.

Multivariate logistic regression analysis found that PLT, GGT, Glu and PT were independent predict factors for obese MAFLD in non-lean patients. Among them, the OR values of PLT, Glu and PT were 1.005 (0.999, 1.011), 1.392 (1.005, 1.926) and 4.265 (2.462, 7.388), respectively, which were all risk factors for the occurrence of obese MAFLD, see Table 3. After deducting the influence of the above four factors, there was no significant association between gender, ALT, AST and other factors and the occurrence of obese MAFLD.

2. Noninvasive indicators of steatosis and fibrosis in overweight and obese MAFLD

The APRI and FIB-4 indexes of the overweight MAFLD patients were higher than those of the obese MAFLD group, and the difference was statistically significant (P<0.05). There was no significant difference in the CAP and LSM between the two groups (P>0.05). (Table 4).

3. Histopathological characteristics of liver in overweight and obese MAFLD groups

Compared with overweight MAFLD, the proportion of moderate to severe inflammatory activity (≥A2) in obese MAFLD patients was significantly higher, but the proportion of significant fibrosis (≥F2) in obese MAFLD patients was significantly lower (P<0.05). However, there was no statistically difference in the proportion of significant steatosis (≥S2) between the two groups, as shown in Table 5.

4. Logistic regression analysis of moderate to severe fibrosis in non-lean MAFLD

Taking the moderate to severe of fibrosis (≥F2) in non-lean MAFLD as the dependent variable and the factors with statistical differences in univariate analysis as the independent variables, a multivariate logistic regression analysis was performed. The results showed that AST, BMI, ALT and CHOL were independent influencing factors of fibrosis in non-lean MAFLD. Among them, the OR value of AST was 1.057 (1.024, 1.090), which was a risk factor for fibrosis in non-lean MAFLD (see Table 6).

5. Diagnostic efficacy of various non-invasive methods for moderate to severe fibrosis in non-lean MAFLD

Generate regression equations of AST, BMI, ALT and CHOL according to the logistic regression model：9.025 - 0.144 * BMI - 0.014 * ALT + 0.055 * AST - 1.476 * CHOL. The regression equation was used as four combined indicators to diagnose moderate to severe fibrosis in non-lean MAFLD patients. The results showed that compared with the traditional FIB-4 (AUC=0.770) and APRI (AUC=0.791) indices, the new combined index was more effective in diagnosing moderate to severe fibrosis in non-lean MAFLD patients, AUC=0.869, see Figure 1.

MAFLD is a newly proposed diagnosis of fatty liver disease that is more applicable to clinical practice than before ^[10]. According to BMI, non-lean MAFLD patients were divided to overweight and obese subgroups. Logistic regression models revealed that obese MAFLD was associated with PLT, GGT, Glu and PT. Compared with overweight MAFLD patients, obese MAFLD patients had higher levels of peripheral blood PLT, PT and Glu, and a higher proportion of histologically moderate to severe inflammatory activity levels. However, GGT level in obese MAFLD group was lower than those in overweight MAFLD group.

With the increase in BMI and CAP, the PLT showed a decreasing trend ^[11,12], but some studies have also reached the opposite conclusion as we have ^[13]. Platelets participate in the inflammatory response of the liver and can promote leukocyte recruitment and activation of effector cells through hepatic sinuses. Moreover, the function and morphology of platelets will also change in patients with diabetes and metabolic syndrome ^[14]. Average platelet volume is directly related to the histological severity of live fibrosis ^[15]. GGT is a liver enzyme, which can help diagnose liver injury. Xing Y et al shown that there was a progressive increase in the prevalence of MAFLD with increasing tertiles of GGT/HDL ^[16], which was not consistent with the study. Increased Glucose is considered an important component of metabolic syndrome. The association of the prevalence of MAFLD with impaired Glucose metabolism has been reported in both children and adult. The prevalence of NASH in obesity children was closely related to high BMI, gender, insulin resistance and hyperuricemia ^[17]. Fasting blood-Glucose was positively associated with BMI in adult patients with NAFLD^[18]. Furthermore, Type 2 diabetes increases the risk of serious NASH and advanced fibrosis in NAFLD patients^[19]. Liver hepatocytes are involved in the synthesis of most blood coagulation factors. In patients with NAFLD, FVIII, FIX, FXI and FXII activities are increased. The relationships between NAFLD and these coagulation factors are independent of age, gender and BMI, which suggest that NAFLD can contribute to the risk of thrombosis^[20].

Although previous meta-analyses have confirmed that obese MAFLD patients have significantly higher metabolic-related serological markers than lean (BMI< 25 kg/m²) patients ^[21], a late-stage fibrosis relationship between non-obese and obese MAFLD persists dispute. A meta-analysis suggested that obesity may predict poor long-term prognosis in MAFLD patients, however, obesity may not be an independent factor for developing NASH or advanced fibrosis in MAFLD patients ^[22]. In the study, APRI and FIB-4 index levels were lower, and the proportion of histologically significant fibrosis was also lower in obese MAFLD compared to overweight MAFLD. We also found that the combined index composed of AST, BMI, ALT and CHOL is more effective in diagnosing significant fibrosis in non-lean MAFLD patients than traditional FIB-4 and APRI. Published studies suggested that blood cholesterol levels were relatively reduced in mice due to inflammation promoting abnormal accumulation of cholesterol from the blood to the liver ^[25,26]. Cheng-Maw Ho et al. also found that free cholesterol and oxidized low-density lipoprotein co-localize on the portal vein wall, and their accumulation in periportal and sinus fibrosis is associated with local stellate cell activation and chicken-wire fibrosis. The accumulation of free cholesterol (FC) is associated with the activation of Hematopoietic stem cells, and FC sensitizes cells to TGF-β through TLR4 up-regulation and down-regulation of the TGF-β pseudoreceptor, resulting in TGF-β-induced liver fibrosis ^[27,28].

Our study has several limitations. First, we did not assess the influence of body fat distribution (eg waist circumference, abdominal circumference, waist-to-hip ratio), and lifestyle factors. Second, there was patient selection bias, because patients with MAFLD who underwent liver biopsy were more likely to consider non-alcoholic steatohepatitis and were generally associated with elevated transaminases. Other morbidly obese MAFLD patients, mostly young women with low transaminase levels, were biopsied during bariatric surgery. Third, the main body of the study is non-lean MAFLD, and there is a lack of normal-weight controls. More data or studies are needed to clarify the differences between non-obese and overweight and obese MAFLD.

In conclusion, overweight and obese MAFLD have different clinical features in terms of laboratory indicators and pathology, especially obese MAFLD manifests as low fibrosis level. AST, BMI, ALT and CHOL provides a better model to predictor is more effective in the diagnosis of fibrosis stage≥F2 in non-lean patients with MAFLD patients.

ALT: alanine transaminase

APRI: aspartate aminotransferase to platelet ratio

AST: aspartate transaminase

BMI: Body Mass Index

CHOL: total cholesterol

FIB-4: fibrosis-4

GGT: gamma-Glutamyl transpeptidase

Glu: Glucose

NAFLD: non-alcoholic fatty liver disease

MAFLD: metabolic associated fatty liver disease

MetS: metabolic syndrome

PLT: platelet

PT: prothrombin time

Contributions

Min-ran Li and Jin-zhong Li searched the literature and conceived of the study, Zhi-yong Dong, Er-hei Dai and Cun-chuan Wang designed the study, and Min-ran Li and Jin-zhong Li interpreted the results and drafted the report. Li-hong Ye, Hai-cong Hai and Zhi-quan Liu made pathological diagnoses of needle-biopsied liver tissue. Xue-dong Zhang performed laboratory test. Yun-yan Liu, Dong-yu Zeng, De-hua Wang, Liu Yang, Jie-ying Li, Yang Cao, Yun Pan and Xun-ge Lin collected the data. Min-ran Li, Jin-zhong Li, Rui-kun Yuan, Xu-jing Liang and Tao-yuan Li analyzed the data. Calvin Pan revised the manuscript and addressed the reviewers’ comments.

Ethics declarations

This study was approved by the Medical Ethics Committee of The Fifth Hospital of Shijiazhuang (approval number: LL2016003) and the Medical Ethics Committee of The First Affiliated Hospital of Jinan University (approval number: KY-2022-048)

Funding and grant support

Youth Program of the National Nature Science Foundation of China (grant number 82000556)

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Table 1 Comparison of general data between overweight and obese MAFLD group

Group	All patients (n=184)	Overweight group（n=65）	Obese group（n=119）	Statistics	*P value
Gender(male/female)	80/104	36/29	44/75	χ2 =5.80	0.01
Age M (P25, P75)	36(29, 49)	40（28, 51）	34（30, 44）	Z=-1.83	0.07
Diabetes or abnormal blood sugar（%）	28.8	21.5	32.8	χ2 =2.59	0.11
Hypertension（%）	25.0	16.9	29.4	χ2 =3.50	0.06
drinking history（%）	9.8	4.6	12.6	χ2 =1.04	0.08

*P value for overweight group vs. obese group

Table 2 Comparison of laboratory parameters between overweight and obese MAFLD groups

Project	Overweight group （n = 65）	Obese group （n=119）	Statistics	P value
WBC[M（P25, P75）,×10⁹/L]	5.93±1.64	7.70±2.80	5.37	0.00
RBC[M（P25, P75）,×10¹²/L]	4.79±0.56	4.96±0.73	1.59	0.11
Hb（xˉ± s ,g/L）	144.39±18.65	139.84±20.43	-1.48	0.14
PLT（xˉ± s ,×10⁹/L）	226.03±74.97	274.19±84.60	3.81	0.00
ALT（U/L）	145.93(59.45, 172.30)	85.22(32.00, 113.05)	-4.10	0.00
AST（U/L）	84.65(39.45, 94.15)	49.49(21.50, 57.10)	-5.15	0.00
TB（μmol/L）	16.98(10.00, 19.00)	13.43(9.35, 15.10)	-2.31	0.02
DB（μmol/L）	6.02(3.70, 6.73)	4.20(2.40, 4.90)	-4.04	0.00
ALB（g/L）	47.33±4.56	43.23±4.01	-6.15	0.00
PA（g/L）	261.21±68.93	241.03±62.04	-1.81	0.07
GLB（g/L）	27.09±5.75	29.21±4.85	2.54	0.01
GGT（U/L）	128.23(43.98, 140.03)	65.52(27.00, 80.50)	-4.16	0.00
ALP（U/L）	91.28±44.20	89.73±42.06	-0.22	0.83
UA（μmol/L）	365.08±97.79	422.71±120.91	2.95	0.00
GLU（mmol/L）	6.06±1.32	7.54±4.93	3.04	0.00
TG（mmol/L）	2.80(1.14, 2.50)	2.29(1.30, 2.32)	-0.16	0.87
CHOL（x± s，mmol/L）	4.94±0.94	5.25±1.12	1.87	0.06
HDL-C（mmol/L）	1.08±0.23	1.11±0.60	0.35	0.73
LDL-C（x±s，mmol/L）	3.09±0.7	3.13±0.91	0.30	0.77
CHE	9625.69±2053.87	10224.81±2087.72	1.71	0.09
Urea	4.45±1.00	4.40±1.11	-0.25	0.80
Cr	62.87±13.21	60.95±15.30	-0.66	0.51
PT	11.15±0.78	12.56±1.26	8.97	0.00
INR	0.97±0.11	0.98±0.09	0.91	0.36
AFP	5.50(2.09, 4.37)	3.00(2.13, 3.67)	-0.77	0.44

Table 3 Multivariate logistic regression analysis for prediction of obses MALFD in non-lean patients

Influencing factors	B	OR	P	95% CI
PLT	0.005	1.005	0.105	0.999-1.011
GGT	-0.007	0.993	0.045	0.986-1.000
GLU	0.330	1.392	0.046	1.005-1.926
PT	1.451	4.265	0.00	2.462-7.388

Table 4 Comparison of non-invasive indicators of steatosis and liver fibrosis between overweight and obese MAFLD groups

Group	APRI [M（P₂₅, P₇₅）]	FIB-4 [M（P₂₅, P₇₅）]	CAP （x±s, dB/m)	LSM （x±s，kPa）
Overweight group（n = 65）	1.18（0.27，1.46）	1.69（0.66，1.84）	283.50±31.63	13.36（8.05，17.00）
Obese group（n=119）	0.67（0.23，0.72）	1.01（0.39，0.95）	306.71±43.59	12.38（4.85，15.98）
Statistics	-5.64	-4.67	-1.55	1.57
P value	<0.001	<0.001	0.12	0.12

Table 5 Comparison of histopathology between overweight and obese MAFLD groups

Group	Steatosis		Activity		Fibrosis
	S0 ~ S1	S2 ~ S3	A0 ~ A1	A2 ~ A4	F0 ~ F1	F2 ~ F4
Overweight group（n = 65）	33	32	25	40	39	26
Obese group（n=119）	62	57	22	97	96	23
χ2 value	0.03		8.82		9.19
P value	0.86		0.003		0.002

Table 6 Multivariate logistic regression analysis of fibrosis stage≥F2 in non-lean MAFLD

Influencing factors	B	OR	P	95% CI
AST	0.055	1.057	0.001	1.024-1.090
BMI	-0.144	0.866	0.005	0.783-0.958
ALT	-0.014	0.986	0.015	0.975-0.997
CHOL	-1.476	0.228	0.001	0.097-0.541

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Clinical features of metabolism-related fatty liver disease in the non-lean population

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