Non-alcoholic fatty liver disease connections with fat-free tissues: A focus on bone and skeletal muscle

Table 1 Studies exploring the association between non-alcoholic fatty liver disease and bone mineral density

Ref.	Study population and sample size	Race/ethnicity	NAFLD assessment	Skeleton: segments	Main findings: BMD
Xia et al[11], 2016	Elderly men (n = 755) and postmenopausal women (n = 904) divided into quartiles of liver fat content (LFC)	Chinese	Liver quantitative US	Lumbar spine, hip, whole body	BMD in any skeletal segment was lower in the highest LFC quartile compared to the lowest quartile. LFC inversely correlated with BMD (all skeletal segments)
Cui et al[12], 2013	Men with NAFLD (n = 46) vs male controls (n = 53); postmenopausal women with NAFLD (n = 73) vs female controls (n = 52)	Chinese	Liver US	Lumbar spine, right hip, femoral neck	Lower BMD at the right hip in participants with NAFLD than controls (in both genders); lower BMD at the femoral neck in men with NAFLD vs controls. Negative association between NAFLD and BMD
Lee et al[13], 2016	Men with NAFLD (n = 1288) vs male controls (n = 2018); postmenopausal women with NAFLD (n = 1217) vs female controls (n = 2112)	Korean	Liver US	Lumbar spine and femoral neck	Negative association between femoral neck BMD and NAFLD in men; positive correlation between lumbar spine BMD and NAFLD in postmenopausal women
Moon et al[14], 2012	Premenopausal women with NAFLD (n = 162) vs controls (n = 54), and postmenopausal with NAFLD (n = 102) vs controls (n = 163)	Korean	Liver US	Lumbar spine	Higher BMD in the control group than postmenopausal women NAFLD; NAFLD negatively associated with BMD in postmenopausal women, but not premenopausal women
Purnak et al[15], 2012	Men (n = 52) and women (n = 50) with NAFLD vs healthy men (n = 28) and women (n = 26)	Caucasian	Liver US	Femur (neck, trochanter, intertrochanteric region and total femur) and lumbar spine	Lower lumbar spine and femoral neck BMD Z-scores in women with high ALT levels
Bhatt et al[16], 2013	Men (n = 129) and women (n = 33) with NAFLD vs controls (men, n = 109; women, n = 64)	Indian	Liver US	Trunk, pelvis, spine, whole body	Higher BMD values in NAFLD subjects than controls
Yang et al[17], 2016	Men with NAFLD (n = 249) vs male controls (n = 610)	Korean	Liver US	Right Hip	NAFLD negatively associated with right-hip BMD
Pacifico et al[18], 2013	Obese children with NAFLD (boys, n = 24, and girls, n = 20) vs obese controls (boys, n = 24, and girls, n = 20)	Caucasian	MRI + liver biopsy	Lumbar spine and whole body	Lower lumbar BMD Z-score in NAFLD children than controls. Negative association of lumbar BMD and whole-body BMD Z-scores with NASH
Pardee et al[19], 2012	Obese children( 10-17 yr) with (n = 38) or without (n = 38) NAFLD	Mixed (89.5% Hipanic, 10.5% non-Hispanic, White)	Liver biopsy	Whole body	Lower whole body BMD Z-score in children with NAFLD than children without NAFLD. Lower whole body BMD Z-score in children with NASH than children without NASH
Chang et al[20], 2015	Obese children and adolescents with NAFLD (n = 15) vs obese children and adolescents with NASH (n = 47) vs controls (n = 32)	Korean	Liver US (NAFLD); liver US + elevated serum aminotransferase levels (NASH)	Arm, leg, trunk, whole body	Age-matched BMD Z-scores were not different between groups
Pirgon et al[21], 2011	Obese children with NAFLD (boys, n = 19, and girls, n = 23) vs obese children (boys, n = 18, and girls, n = 22) and lean children (boys, n = 15, and girls, n = 15)	Caucasian (Turkish)	Liver US	Lumbar spine	Lower lumbar BMD-SDS in obese adolescents with NAFLD compared with obese and lean adolescents without NAFLD
Campos et al[22], 2012	Obese adolescents with NAFLD (n = 18) vs obese adolescents without NAFLD (n = 22)	Brazilian	Liver US	Whole body	Obese adolescents with NAFLD had a significantly lower values of BMC than their counterparts without NAFLD. No differences in BMD Z-scores

BMC: Bone mineral content; BMD-SDS: Bone mineral density-standard deviation score; BMD: Bone mineral density; LFC: Liver fat content; MRI: Magnetic resonance imaging; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; US: Ultrasound; ALT: Alanine aminotransferase.

Table 2 Studies exploring the association between non-alcoholic fatty liver disease and skeletal muscle mass

Ref.	Study population and sample size	Race/ethnicity	NAFLD assessment	Skeletal muscle mass assessment	Main findings: skeletal muscle
Hong et al[6], 2014	Men (n = 32) and women (n = 96) with sarcopenia vs men (n = 135) and women (n = 189) without sarcopenia	Korean	LAI	DXA:	Increased ORs of NAFLD in individuals with SMI value in the lower quartiles
				-SMI = SMM/weight (%)
Koo et al[25], 2016	Adults with NAFLD (n = 117) vs adults with NASH (n = 123) vs controls (n = 69)	Korean	Liver biopsy, Fibroscan	BIA:	Lower ASM (%) and ASM/BMI in NAFLD and NASH than controls; higher prevalence of sarcopenia in NAFLD and NASH groups than control group
				-ASM (kg)
				-ASM/weight (%)
				-ASM/BMI
Lee et al[26], 2015	Men (n = 5617) and women (n = 9515) divided into four groups: sarcopenic obese (n = 2455) vs non-sarcopenic obese subjects (n = 2198); sarcopenic non-obese (n = 2004) vs non-sarcopenic non-obese subjects (n = 8475)	Korean	For NAFLD: HSI, CNS	DXA:	Inverse correlation between all indices of NAFLD and SMI
			For fibrosis: BARD, FIB-4	-ASMI = ASM/weight (%)	Increased ORs of NAFLD and advanced fibrosis in subjects with sarcopenia
Hashimoto et al[27], 2016	Diabetic men with NAFLD (n = 58) vs controls (n = 21), and diabetic women with NAFLD (n = 39) vs controls (n = 27)	Japanese	CAP	BIA:	Negative association between CAP and SMI in men; no significant association in women
			FIB-4	-SMM (kg)
				-SMI = SMM/weight (%)
Moon et al[28], 2013	Low FLI group (men = 1641, and women, n = 1180) vs intermediate FLI group (men, n = 2600, and women, n = 2296) vs high FLI group (men, n = 1052, and women, n = 796)	Korean	FLI	BIA:	Lower SMI in the high FLI group and the intermediate FLI group than the low FLI group. Negative correlation between FLI and SMI, and between FLI and SVR. The highest SVR quartile had a lower OR for FLI ≥ 60
				-SMI = SMM/weight (%)
				-SVR = SMM/VFA
Kim et al[29], 2016	FLI ≥ 60 group (men, n = 208, and women, n = 181) vs FLI < 60 group (men, n = 976, and women, n = 2374)	Korean	FLI	DXA:	Lower SMI in the high FLI group than the low FLI group in both genders. Increased ORs for FLI-defined NAFLD in men and women with low SMI
				-ASM (kg)
				-SMI = ASM/weight (%)
Lee et al[30], 2016	Men (n = 1241) and women (n = 1520) with NFLS-based NAFLD divided into two groups: sarcopenic subjects (n = 337) v. non-sarcopenic subjects (n = 2424)	Korean	For NAFLD: NLFS, CNS,HSI;	DXA:	Higher NFS, FIB-4, and Forns index in the sarcopenic group that the non-sarcopenic group; negative association of SI with NFS, FIB-4, and Forns index
			For fibrosis: NFS, FIB-4, Forns index	-SI = ASM/BMI
Poggiogalle et al[31], 2016	Obese men (n = 81) and women (n = 346) divided into 2 groups: FLI 20 ≤ FLI < 60 (n = 61) and FLI ≥ 60 (n = 359) (FLI ≤ 20 in 7 subjects only, excluded from the analysis)	Caucasian (Italian)	FLI	DXA:	Positive association between FLI and TrFM/ASM ratio (indicating high visceral adiposity and low appendicular muscularity)
				-TrFM/ASM ratio

ASM: Appendicular skeletal mass; ASMI: Appendicular skeletal mass index; BMI: Body mass index; CAP: Controlled attenuation parameter; CNS: Comprehensive NAFLD score; CT: Computed tomography; FLI: Fatty liver index; HIS: Hepatic steatosis index; LAI: Liver attenuation index; NAFLD: Non-alcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; NFS: NAFLD fibrosis score; SI: Sarcopenia index; NLFS: NAFLD liver fat score; SMI: Skeletal muscle index; SMM: Skeletal muscle mass; SVR: Skeletal muscle to visceral fat ratio; TrFM: Truncal fat mass; VFA: Visceral fat area.