Outcomes of liver and cardiovascular metabolic diseases among lean vs non-lean individuals with metabolic dysfunction-associated steatotic liver disease

Table 1 Cardiovascular-kidney-metabolic syndrome stages

Stages	Definition
Stage 0: No CKM risk factors	Individuals with normal BMI and waist circumference, normoglycemia, normotension, a normal lipid profile, and no evidence of CKD or subclinical or clinical CVD
Stage 1: Excess or dysfunctional adiposity	Individuals with overweight/obesity, abdominal obesity, or dysfunctional adipose tissue, without the presence of other metabolic risk factors or CKD. BMI ≥ 25 kg/m2 (or ≥ 23 kg/m2 if Asian ancestry), waist circumference ≥ 88/102 cm in women/men (or if Asian ancestry ≥ 80/90 cm in women/men), or fasting blood glucose ≥ 100-124 mg/dL or HbA1c between 5.7% and 6.4%
Stage 2: Metabolic risk factors and CKD	Individuals with metabolic risk factors, hypertriglyceridemia (≥ 135 mg/dL), hypertension, MetS, diabetes, or CKD
Stage 3: Subclinical CVD in CKM	Subclinical ASCVD or subclinical HF among individuals with excess/dysfunctional adiposity, other metabolic risk factors, or CKD. Subclinical ASCVD to be principally diagnosed by coronary artery calcification (subclinical atherosclerosis by coronary catheterization/computed tomography angiography also meets criteria). Subclinical HF diagnosed by elevated cardiac biomarkers (NT-proBNP ≥ 125 pg/mL, hs-troponin T ≥ 14 ng/L for women and ≥ 22 ng/L for men, hs-troponin I ≥ 10 ng/L for women and ≥ 12 ng/L for men) or by echocardiographic parameters, with a combination of the 2 indicating highest HF risk. Risk equivalents of subclinical CVD. Very high-risk CKD (stage G4 or G5 CKD or very high risk per KDIGO classification). High predicted 10-year CVD risk
Stage 4: Clinical CVD in CKM	Clinical CVD (coronary heart disease, HF, stroke, peripheral artery disease, atrial fibrillation) among individuals with excess/dysfunctional adiposity, other CKM risk factors, or CKD. Stage 4a: No kidney failure. Stage 4b: Kidney failure present

CKM: Cardiovascular-kidney-metabolic syndrome; CKD: Chronic kidney disease; CVD: Cardiovascular disease; BMI: Body mass index; HbA1c: Glycated hemoglobin; MetS: Metabolic syndrome; ASCVD: Atherosclerotic cardiovascular disease; HF: Heart failure; NT-proBNP: N-terminal pro-B-type natriuretic peptide; KDIGO: Kidney Disease: Improving Global Outcomes.

Table 2 Summary of articles included in the study

Ref.	Study design	Participants (n)	Age (mean ± SD)	Sex (male/female)	Region (country)	Definition of lean	Outcomes of interest investigated
[15]	Cross-sectional	465	40.8 ± 9.9	118/283	Asia (Bangladesh)	Not defined	Steatosis, MASH, and fibrosis
[16]	Systematic review and meta-analysis	54441	45.6	2320/1592	Unspecified	BMI < 23 kg/m2	MASLD occurrence, fibrosis
[21]	Retrospective cohort	669	Lean (46 ± 13); non-lean (49 ± 12)		Europe (Italy)	BMI < 25 kg/m2	MASH, steatosis, fibrosis, HTN
[17]	Prospective cohort	2117	48.2 ± 13.7	402/244	Europe (Sweden)	BMI < 25 kg/m2	MASH, fibrosis, steatosis, HTN, CVD
[18]	Case-control	307			Asia	BMI < 25 kg/m2	Fibrosis
[19]	Prospective cohort	307			Asia	Unspecified	Fibrosis, liver failure
[9]	Retrospective cohort	1040	Lean (38.5 ± 12.04); non-lean (41.46 ± 11.14)	604/436	Asia (India)	BMI < 23 kg/m2	MASH, fibrosis, steatosis, HTN
[20]	Cross-sectional	10576383		2347669/17345	Worldwide (24 countries)	BMI < 25 kg/m2	MASH, fibrosis, steatosis, HTN, CVD
[22]	Cross-sectional	124		69/67	Europe (Germany)	BMI < 25 kg/m2	Steatosis, MASH
[23]	Case-control	390	Control (47.5 ± 13), MASLD (52 ± 8), MASH (51.7 ± 9)	141/159	South America (Argentina)	BMI < 25 kg/m2	Fibrosis, MASH
[24]	Cross-sectional	162	All participants 47 ± 14	96/66	Europe (Greece)	BMI < 25 kg/m2	MASH, fibrosis
[25]	Cross-sectional	1777	Control (48), lean MASLD (40), obese (49)	817/960	Europe (Belgium)	BMI < 25 kg/m2	HTN, fibrosis, MASH, steatosis
[26]	Cross-sectional	4834	Lean (51.5 ± 18.0); non-lean [overweight (54.1 ± 15.7), obese (51.0 ± 14.1)]	2220/2614	North America (United States)	BMI < 25 kg/m2	Cirrhosis, death
[27]	Retrospective cohort	18594	Lean (51.0 ± 36, 63); non-lean [overweight (52.5 ± 41, 63), obese (52.0 ± 40, 61)]	8767/9827	North America (United States)	BMI < 25 kg/m2	Cirrhosis, death, CVD
[28]	Cross-sectional	3386	56.9 ± 13	1402/1984	North America (United States)	BMI < 25 kg/m2	Cirrhosis, CVD
[29]	Meta-analysis	23514	53.2 ± 6.8	14814/8700	North America (United States)	BMI < 25 kg/m2	CVD, death
[10]	Retrospective cohort	581	Lean (58 ± 12); non-lean (59 ± 11)	330/251	Asia (Japan)	BMI < 23 kg/m2	CVD, HTN
[30]	Prospective cohort	394		173/221	North America (United States)	BMI < 25 kg/m2	CVD
[31]	Prospective cohort	1339	48	2320/1430	Worldwide	BMI < 25 kg/m2	Fibrosis, CVD
[11]	Prospective cohort	2985		703/1227 (excluded control group)	Asia (Sri Lanka)	BMI < 23 kg/m2	CVD
[32]	Prospective cohort study	1312	MASLD cohort (49.5 ± 13.5), control (52.4 ± 5.8)	762/550	Europe (Austria)	BMI ≤ 25 kg/m2	Steatohepatitis, fibrosis, CVD, death
[33]	Retrospective cohort	446		268/178	Asia (Japan)	BMI < 25 kg/m2	CVD, HTN
[12]	Retrospective cohort study	1647	Non-overweight (50.0 ± 7.9), Overweight (48.8 ± 8.9)	941/706	Asia (Japan)	BMI < 23 kg/m2	CVD, HTN
[26]	Cross-sectional	4834	Normal weight (51.5 ± 18.0), overweight (54.1 ± 15.7), obese (51.0 ± 14.1)	2220/2614	North America (United States)	BMI ≤ 25 kg/m2	CVD, cirrhosis, death
[34]	Cross-sectional	3410	Lean (51.5), non-lean (50.0)	1460/1950	North America (United States)	BMI ≤ 25 kg/m2	CVD, HTN
[13]	Cross-sectional	743	Lean MASLD (75.0 ± 10.7). Non-lean MASLD (66.8 ± 11.9)	309/434	Asia (Thailand)	BMI < 23 kg/m2	Fibrosis, HTN
[14]	Cross-sectional	2144	56.1 ± 9.3	1359/785	Asia (Korea)	BMI < 23 kg/m2	CVD, HTN
[35]	Prospective cohort	1261		699/563	Asia (Saudi Arabia)	BMI ≤ 25 kg/m2	CVD, HTN
[36]	Cross-sectional	2238	Lean without MASLD (56.76 ± 9.9); lean with MASLD (60.36 ± 10.2); overweight MASLD (61.36 ± 9.5); obese MASLD (61.66 ± 9.8)	1158/1080	Europe (Austria)	BMI ≤ 25 kg/m2	CVD, HTN
[38]	Cross-sectional	9341	Full sample (43.64 ± 0.37)	4474/4867	North America (United States)	BMI ≤ 25 kg/m2	Mortality, CVD
[37]	Cross-sectional	14365		6730/7635	North America (United States)	BMI ≤ 25 kg/m2	Mortality, CVD

MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; BMI: Body mass index; CVD: Cardiovascular disease; HTN: Hypertension.