Non-alcoholic fatty liver disease and diabetes: From physiopathological interplay to diagnosis and treatment

Table 1 Studies with histopathological evaluation of diabetic patients with non-alcoholic fatty liver disease

Ref.	Sample size	Metabolic syndrome and its components	Diabetes duration (yr)	Diabetes-related complications	Elevated enzyme levels AST/ALT/GGT	Risk factors for NASH	Fibrosis
Amarapurka et al[12]	36						30.5%
Gupte et al[13]	32				ALT and/or AST 31%	No risk factors	22%
Kemmer et al[38]	22 (females)					No risk factors
Leite et al[6]	92	Hypertension 88%	7.8	Microvascular 46%	14%/16%/13%	Hypertriglyceridemia High ALT	34%-60%
		Dyslipidaemia 86%		Macrovaascular 26%		Low HDL-chol
Prashanth et al[5]	83	Metabolic syndrome 77%	8.2		ALT 7%	MS components	37%
						High ALT
						High AP

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gammaglutamyltransferase; AP: Alkaline phosphatase; NASH: Non-alcoholic steatohepatitis; HDL-chol: HDL-cholesterol.

Table 2 Current data on non-pharmacological treatments of non-alcoholic fatty liver disease

Ref.	Sample size	Type 2 diabetes	Type of intervention	Study design/duration	Liver enzymes	Imaging	Histology
Kistler et al[111]	813 adults	25%	Inactive or moderate or vigorous exercise	Retrospective analysis of biopsy-proven NAFLD	Vigorous recommendations was associated with ↓ GGT levels compared with being inactive		Vigorous exercise was associated with a ↓ adjusted odds of NASH
Hallsworth et al[112]	19 adults		Resistance exercise	Randomly assigned to either exercise or standard care. 8 wk	No significant changes in ALT levels	Resistance exercise: 13% relative ↓ in liver lipid by 1H-MRS
Bacchi et al[113]	31 adults	100%	Aerobic (AER) or resistance (RES) training	Randomized controlled study. 4 mo		Hepatic fat content was ↓ in both by in-opposed-phase MR imaging
Mathurin et al[114]	381 adults	25%	Bariatric surgery	Prospective study. Follow-up of 5 yr	Significant ↓ in ALT and GGT levels 1 and 5 yr after bariatric surgery		Significant ↓ in NASH
							Fibrosis ↑, 96% with F1
Mummadi et al[115]	766 paired liver biopsies		Bariatric surgery	Systematic review and meta-analysis (15 studies)			↓ or resolution 81.3% in NASH and 65.5% in fibrosis

↓: Decrease; ↑: Increase. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gammaglutamyl transferase; AP: Alkaline phosphatase; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis;

¹H-MRS: Proton magnetic resonance spectroscopy; F1: Stage 1 of fibrosis.

Table 3 Current data on pharmacological treatments of non-alcoholic fatty liver disease

Ref.	Sample size	Type 2 diabetes	Type of intervention/ drug	Study design/duration	Liver enzymes	Imaging	Histology
Parker et al[116]	355		Omega-3 PUFA: 0.8-13.7 g/d	Systematic review and meta-analysis (9 studies) median duration of treatment: 6 mo	Significant efficacy of PUFA on ALT and AST levels	Significant efficacy of PUFA on liver fat (US, 1H-MRS)
Lindor et al[119]	166		UDCA: 13-15 mg/kg per day	Randomized placebo-controlled study (24 mo)	No significant changes in ALT, AST and GGT levels with UDCA		No significant changes in NASH or fibrosis with UDCA
Leuschner et al[120]	185		UDCA: 23-28 mg/kg per day	Randomized placebo-controlled study (18 mo)	No significant changes in ALT and AST, ↓ GGT levels with UDCA		No significant changes in NASH or fibrosis with UDCA
Uygun et al[121]	36	0%	Metformin: 1.7 g/d	Randomized placebo-controlled study (6 mo)	Significant ↓ in ALT and AST levels with metformin	Significant efficacy of metformin on liver fat (US)	No significant ↓ in inflammatory activity or fibrosis with metformin
Haukeland et al[122]	48	27%	Metformin: 2.5-3 g/d	Randomized placebo-controlled study (6 mo)	No significant changes in ALT, AST levels with metformin	No significant ↓ on liver fat (CT) with metformin	No significant changes in NASH with metformin
Shields et al[123]	19	0%	Metformin: 500 mg-1 g/d	Randomized placebo-controlled trial (12 mo)	No significant changes in ALT and AST levels with metformin		No significant changes in NASH or fibrosis with metformin
Lutchman et al[126]	18	0%	Pioglitazone: 30 mg/d	Prospective open study (12 mo)	ALT levels normalized in 72%	Hepatic fat content was ↓ by MR imaging	significant ↓ in necroinflammation and fibrosis with pioglitazone
Belfort et al[127]	55	48%	Pioglitazone: 45 mg/d	Randomized placebo-controlled study (6 mo)	Significant efficacy of pioglitazone on ALT and AST levels	Significant efficacy of pioglitazone on liver fat (1H-MRS)	Significant ↓ in necroinflammation but not in fibrosis with pioglitazone
Aithal et al[128]	74	0%	Pioglitazone: 30 mg/d	Randomized placebo-controlled trial (12 mo)	Significant ↓ in ALT and GGT levels		Significant ↓ in inflammatory activity and fibrosis with pioglitazone
Sanyal et al[129]	247	0%	Vitamin E: 800 UI/dPioglitazone: 30 mg/d	Randomized placebo-controlled trial (24 mo)	Significant ↓ in ALT, AST and GGT levels with both treatments		Significant ↓ of NASH with vitamin E. No changes in fibrosis with either treatment

↓: Decrease; ↑: Increase. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gammaglutamyl transferase; AP: Alkaline phosphatase; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; PUFA: Polyunsaturated fatty acids; UDCA: Ursodeoxycholic acid; US: Ultrasonography; MR: Magnetic resonance;

¹H-MRS: Proton magnetic resonance spectroscopy; CT: Computed tomography.