Relation between cortisol and metabolic dysfunction-associated steatotic liver disease: A dog chasing its tail

Table 1 Studies reporting prevalence of metabolic dysfunction-associated steatotic liver disease in patients with endogenous hypercortisolism

Ref.	Number of patients	Patients	MASLD criteria for diagnosis	Results	Additional findings and comments
Marengo et al[33]	49	27 CS; 10 adrenal adenoma; 6 adrenal hyperplasia; 1 ACC; 5 ectopic ACTH	Reported on ultrasound. TC (liver/spleen attenuation ratio)	26% of liver steatosis	MASLD appears to be more frequent in adrenal adenomas. Data on follow up are limited from the small number of patients
Rockall et al[32]	50	50 CS	Liver/spleen attenuation ratio	20% of liver steatosis	The author showed a correlation between hepatic steatosis and abdominal fat area and visceral fat area
Zhou et al[10]	1652	905 CD; 16 ACC; 30 primary pigmented nodular adrenocortical disease; 346 adrenal adenomas; 102 bilateral macronodular adrenal hyperplasia; 98 ectopic; 20 unknown	ICD10 codes	24.5% liver steatosis	The study is retrospective and based on ICD10 codes and therefore there is high risk of bias
Candemir et al[35]	40	40 metabolically healthy MACS	Liver/spleen attenuation ratio	25%	The authors found that DEX1 response is a predictor of MASLD
Yu et al[34]	159	100 MACS; 59 CS	Liver/spleen attenuation ratio	57% in MACS; 66% CS	TyG-index, and HOMA-IR are critical markers in the development of nonalcoholic fatty liver disease in patients with excess cortisol

MASLD: Metabolic dysfunction-associated steatotic liver disease; CS: Cushing’s syndrome; ACC: Adrenocortical cancer; ACTH: Adrenocorticotropic hormone; CD: Cushing’s disease; MACS: Mild autonomous cortisol secretion; TC: Total cholesterol; DEX 1: 1 milligram dexhametasone suppression test; TyG: Triglyceride glucose; HOMA-IR: Homeostasis model assessment of insulin resistance.

Table 2 List of preclinical studies and trial involving 11β-hydroxysteroid dehydrogenase type 1

Compound	Study type	Subjects	Key findings related to liver	Potential indication	Ref.
J2H-1702	Preclinical study	Mice (high fat/high carbohydrate fed)	Decreased triglyceride levels in the liver	MASLD	[82]
INU-101	Preclinical study	Mice (fast-food diet model)	Reduced hepatic lipid accumulation and fibrosis	MASLD and liver fibrosis	[43]
J2H-1702	Preclinical study	Mice (NASH models)	Reduced lipid accumulation and fibrosis	MASH	[41]
BVT2733	Preclinical study	Mice (high fat diet)	Decrease in body weight, better glucose tolerance, reduced inflammation	Obesity-related liver disease	[83]
AZD6925	Preclinical study	Mice	Prevented hepatic steatosis and reduced liver triglycerides levels	MASLD	[84]
BI 135585	Single-dose study and double blind, placebo controlled clinical trial	Healthy volunteers (single dose) and patients with type 2 diabetes	Demonstrated liver 11β-HSD1 inhibition	MASLD in T2D	[85]
BI 187004	Randomized, double-blind, placebo-controlled	Patients with T2D and obesity	Near-full liver 11β-HSD1 inhibition	Liver-related metabolic disorders	[86]
J2H-1702	Randomized, double blinded, placebo-controlled trial	Healthy volunteers	Effectively reduced 11β-HSD1 activity	NASH	[87]
RO5093151	Phase 1b trial. Multicenter, randomized, double-blind, placebo-controlled trial	MASLD patients	Significantly reduced liver-fat content vs placebo	MASLD	[88]
AZD4017	Phase II, randomized, double-blind, placebo-controlled study	NASH or MASLD patients	Reduced conversion of cortisone to cortisol. Able to find a significant difference in reduction of liver fat fraction only in patients with NASH and T2D	MASH with T2D	[48]

MASLD: Metabolic dysfunction-associated steatotic liver disease; NASH: Non-alcoholic steatohepatitis; MASH: Metabolic dysfunction associated steatohepatitis; 11β-HSD1: 11β-hydroxysteroid dehydrogenase type 1; T2D: Type 2 diabetes.

Table 3 Summary of the main enzymes involved in hepatic cortisol metabolism and their role in metabolic dysfunction-associated steatotic liver disease. The table highlights enzyme function, expression changes across disease stages, effects on hepatic steatosis, and potential therapeutic implications

Enzyme	Primary function	Hepatic expression	Effects on hepatic steatosis	Possible therapeutic implications
11β-HSD1	Converts inactive cortisone to active cortisol; amplifies intracellular cortisol action	Reduced in early steatosis; increased in MASH	Overexpression promotes lipogenesis and fat accumulation; knockout protects against steatosis	Inhibition may provide reduction in liver steatosis
11β-HSD2	Inactivates cortisol to cortisone	Not extensively studied in MASLD	Primarily renal/placental function; limited hepatic role in MASLD	Not a primary therapeutic target at the moment for MASLD
5α-reductase type 1	Converts cortisol to 5α-dihydrocortisol (retains some GR activity); converts testosterone to DHT	Increased in steatosis	Deficiency/inhibition increases steatosis but protects against HCC; mediates metabolic effects	Dual inhibitors (dutasteride) increase hepatic lipid accumulation. Selective type 2 inhibitors (finasteride) have no effect on steatosis
5α-reductase type 2	Converts cortisol to 5α-dihydrocortisol; converts testosterone to DHT in reproductive tissues	Primarily reproductive tract expression	Minimal metabolic effects; deficiency does not increase steatosis	Limited metabolic relevance
5β-reductase (AKR1D1)	Converts cortisol to 5β-dihydrocortisol (biologically inactive); major cortisol inactivation pathway	Variable in early disease; reduced with progressive fibrosis	Knockdown promotes lipid accumulation via increased de novo lipogenesis	Increasing its activity may have a potential protective role

MASLD: Metabolic dysfunction-associated steatotic liver disease; 11β-HSD1: 11β-hydroxysteroid dehydrogenase type 1; MASH: Metabolic dysfunction associated steatohepatitis; 11β-HSD2: 11β-hydroxysteroid dehydrogenase type 2; GR: Glucocorticoid receptor; DHT: Dihydrotestosterone; HCC: Hepatocellular carcinoma.