Metabolic dysfunction-associated steatotic liver disease heterogeneity: Need of subtyping

Table 1 Clinical characteristics of metabolic dysfunctions-associated steatotic liver disease subtypes

	Pancreatic dysfunction			Hepatic
	Diabetes mellitus			Non diabetic	Genetics	Mixed
	Non type II diabetes mellitus		Type II DM	Insulin resistance	Monogenic	Overlap
	DM type I	Primary beta cell dysfunctions (monogenic)	Secondary beta cell dysfunctions	Metabolic syndrome	PNPLA3 or TM6SF2 associated steatohepatitis	DM+/-IR+/-Genetics
BMI	Normal	Normal	Obesity	Obesity	Normal	Unknown
DM	Yes	Yes	Yes	May be	No	May be
Triglyceride level	Normal	Normal	High	High	Normal	Unknown
Total cholesterol	Normal	Normal	Normal or high	Normal or high	Normal	Unknown
HDL	Normal	Low	Low	Low	Normal	Unknown
LDL	Normal	Normal	High	High	Normal	Unknown
Fasting Insulin	Very low (< 5)	8-12 (< 10)	8-10 (< 10)	> 15, commonly > 20	Normal	Unknown
Waist ot hip ratio	Normal	Normal	May be	Reversed	Normal	Unknown
Fasting blood glucose (FBG) (pre-DM)	No	No	No	Yes	No	Unknown
HOMA-IR	Normal or minimally high	Normal or minimally high	> 3.0 < 5.0	> 3.0 usually > 7.0	Normal	Unknown
FBG/insulin ratio	> 25	> 15	> 15	< 10	< 10	Unknown
Adiponectin	Normal or high	Unknown	Low	Low	Normal	Unknown
Leptin	Low	Unknown	No association with high levels after adjusted with confounder	High	Normal	Unknown
Other features	Family and personal history of autoimmunity	Family history of DM and onset at young age			Family history of liver disease: Unknown
Prevalence (population)	0.5% to 0.75 %	0.2 % to 0.3 %	0.1	30% to 40% among obese and overweight	Variable depending upon ethnicity/race; highest in hispanics (45%) and lowest in African American. Also depends upon heterozygosity vs homozygosity	Unknown
Disease burden (proportion developing MASLD)	20% (most studies)		55%-76%	70%-75% among overweight and obese. Based upon liver biopsy	10% to 15%	Unknown
Genetics vs acquired	Acquired	Genetics	Acquired	Acquired	Genetics	Unknown
Hepatic steatosis	Yes	Yes	Yes	Yes	Yes	High
Mechanism	DNL	DNL	DNL	Lipolysis of adipose tissue OR familial hypertriglyceridemia leading to increased hepatic uptake	Decreased excretion of VLDL	Multilevel
MASH risk	Low	Low	High	Moderate		Very high
Fibrosis risk	Unknown	Unknown	Higher than non-diabetics	0.22	Higher than non-diabetics and diabetics	Synergistically rises depending upon the number overlaping factors
CAD risk	Yes	Yes	Yes	Yes	No	Unknown
HCC risk	Unknown	Unknown	Higher than non-diabetics	High	High	Very high

BMI: Body mass index; DM: Diabetes mellitus; CAD: Coronary artery disease; HCC: Hepatocellular carcinoma; MASH: Metabolic dysfunction-associated steatoheptatits; VLDL: Very-low-density lipoprotein; DNL: De novo lipogenesis; HOMA-IR: Homeostasis Model Assessment-Estimated Insulin Resistance; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; MASLD: Metabolic dysfunction-associated steatotic liver disease; IR: Insulin resistance.