Metabolic-associated fatty liver disease from childhood to adulthood: State of art and future directions

Table 1 Comparison between metabolic associated fatty liver disease and non-alcoholic fatty liver disease diagnostic criteria

MAFLD criteria[1]	NAFLD criteria[62]
Histological (biopsy), imaging or blood biomarker evidence of hepatic steatosis and the presence of one of these criteria:	Presence of steatosis in > 5% of hepatocytes detected by biopsy
(1) Overweight/obesity	-The proton density fat fraction (providing a rough estimation of the volume fraction of fatty material in the liver) > 5.6% assessed by proton magnetic resonance spectroscopy
(2) Diabetes mellitus
(3) Evidence of metabolic dysregulation defined as the presence of ≥ 2 of the following conditions:
(a) Waist circumference ≥ 102 cm in Caucasian men and 88 cm in women (or ≥ 90/80 cm in Asian men and women);
(b) Blood pressure ≥ 130/85 mmHg or specific drug treatment; (c) triglyceride ≥ 1.70 mmol/L or specific drug treatment;
(d) High-density lipoprotein cholesterol < 1.0 mmol/L for men and < 1.3 mmol/L for women;
(e) Prediabetes (i.e., fasting glucose levels 5.6–6.9 mmol/L, or 2-h postload glucose levels 7.8–11.0 mmol/L or hemoglobin A1c 5.7%–6.4%;
(f) Homeostasis model assessment-insulin resistance score ≥ 2.5;
and (g) High sensitive C-reactive protein > 2 mg/L
	-Quantitative fat/water selective magnetic resonance imaging
	Exclusion of both secondary causes and a daily alcohol consumption ≥ 30 g for men and 20 g for women

MAFLD: Metabolic associated fatty liver disease; NAFLD: Non-alcoholic fatty liver disease.

Table 2 Main findings of the studies on MAFLD genetics

Gene	Study design	Population	Gene pathophysiology	Main findings
b-Klotho (KLB) gene	Panera et al[57], Hospital-based retrospective cohort study	1111 adult Italian MAFLD patients from the Metabolic Liver Diseases outpatient service at Fondazione IRCCS Ca’Granda of Milan between January 1999 and December 2019. Patients were stratified according to obesity status:	The rs17618244 G>A variant in the b-Klotho (KLB) gene encodes for a transmembrane protein which complexes with Fibroblast Growth Factor Receptors to bind the hormones FGF21 and FGF19. Both genes play an important role in lipid and glucose metabolism and in obesity	KLB rs17618244 variant was linked to hepatic fibrosis
		-BMI > 35: 708 subjects		KLB A allele was associated with lobular inflammation and cirrhosis in patients stratified for obesity status; Hepatic KLB mut expression seemed to be linked to proliferative rate improvement and pro-fibrogenic genes induction
		-BMI ≤ 35: 403 subjects
		Inclusion criteria were liver biopsy or severe obesity and availability of DNA samples
Hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene	Liu et al[59], Cross-sectional analysis	427 Han Chinese from the PERSONS cohort with biopsy confirmed MAFLD;	Hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene encodes a hepatic lipid droplet protein	Data confirmed that the HSD17B13 region is a susceptibility locus for MAFLD-related fibrosis
		Aged ≥ 18 yr
				An effect of modulated PNPLA3 rs738409 on hepatic steatosis was reported
				Significant differences in levels of fasting glucose, triglycerides, and high-density lipoprotein cholesterol among subject with HSD17B13- rs72613567 (TA allele) genotypes were observed, but no differences in biochemical parameters among the rs6531975 (A allele) genotypes were found; The minor TA allele was linked to an increased risk of fibrosis, while the minor A allele had a protective effect against liver damage
Membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7)	(1) Meroni et al[52], Review: 21 studies: -6 case control studies; -10 case only; -2 metanalysis; -2 GWAS; -1 cohort studies	(1) Age: -4 pediatric studies; -17 adult studies; Ethnicity: -14 Caucasian; -5 multiethnic; -2 Asian	The MBOAT7 codifies for an enzyme highly expressed in hepatocytes, hepatic stellate cells and hepatic sinusoidal cells; It has been involved in fatty acid metabolism and in hepatic both inflammation and fibrosis	(1) In patients with MAFLD, MBOAT7 might affect liver damage
				Downregulation of liver expression of MBOAT7 induces changes in phosphoinositide composition pattern with subsequent modified membrane lipid composition and lipid mediator profiles
				Hyperinsulinemia, is a cofactor for MBOAT impairment; MBOAT7 dysfunction may influence liver disease progression to steatohepatitis and fibrosis and chronic hyperinsulinemia to steatosis development
	(2) Ismaiel et al[53], Review: 22 studies: -7 case control studies; -3 case only; -5 metanalysis; -7 cohort studies	(2) A total of 22 studies: -4 pediatric studies with ultrasound (US) diagnosis of fatty liver; -18 adult studies: 17 with fatty liver diagnosis with liver biopsy/ imaging and 1 with US		(2) Except for Asian population, studies on European, Hispanic, and African American adults with MAFLD evaluating the rs641738 variant reported a downregulation of the MBOAT7 expression, which increased MAFLD severity, liver fat, NASH progression, advanced fibrosis, and HCC
				No association with coronary artery disease was found. In children with obesity this variant was associated with increased plasma ALT levels

MAFLD: Metabolic associated fatty liver disease; FGFR: Fibroblast growth factor receptor; ALT: Alanine transaminase; MBOAT7: Membrane-bound O-acetyltransferase domain-containing protein 7; US: Ultrasound; GWAS: genome-wide association study.

Table 3 Metabolic syndrome criteria in adults and children

	Abdominal obesity	Hypertension	Dyslipidemia	Fasting glucose
IDF central obesity + 2 of 4 criteria in adult patients and children aged >10 yr[87-89]	10–15 yr old waist circumference (WC) ≥ 90th percentile for age and sex	Systolic BP ≥ 130 mmHg or diastolic BP ≥ 85 mmHg	TG ≥ 150 mg/dL or specific treatment HDL < 40 mg/dL (male), HDL < 50 mg/dL (female)	≥ 100 mg/dL or diagnosis of type 2 diabetes mellitus
	>15 yr old WC ≥ 94 cm (male) b WC ≥ 80 cm (female)
Panel: IDEFICS definition of metabolic syndrome in children aged 2–11 yr[90]1	10–15 yr old WC ≥ 90th percentile for age and sex	Blood pressure: systolic ≥ 90th percentile or diastolic ≥ 90th percentile	TG: ≥ 90th percentile or HDL cholesterol: ≤ 10th percentile	Insulin ≥ 90th percentile or fasting glucose ≥ 90th percentile
	> 15 yr old adults criteria

¹Children would require close monitoring if three or more of these risk factors exceed the 90^th percentile (or ≤ 10^th percentile for HDL cholesterol), and an intervention if three or more of these risk factors exceed the 95^th percentile (or ≤ 5^th percentile for HDL cholesterol).

BP: Blood pressure; HDL: High-density lipoprotein; IDEFICS: Identification and prevention of dietary- and lifestyle-induced health effects in children and infants; IDF: International diabetes federation; TG: Triglycerides; WC: Waist circumference.