Table 1.

Relative incidence and male : female ratio and sex difference in acute and chronic liver diseases. N.a., not available; DILI, drug-induced liver injury; CYP, cytochrome P450; P-gp, P-glycoprotein; NAFLD, non-alcoholic liver disease; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; AIH, autoimmune hepatitis; HCC, hepatocellular carcinoma; TLR, toll-like receptor; PD1, programmed cell death protein 1; PDL1, Programmed death-ligand 1; FA, fatty acid; HLA, human leukocyte antigen; E2, estradiol.

Liver Disease	Relative Incidence Male:Female Ratio	Mechanisms of Sex Differences	Refs.
Acute liver injury
DILI (according to RUCAM)	1:2	Sex-related different bioavailability and excretion of drugs e.g., due to sex hormone activity that affect CYP and P-gp expression Difference in genetic backgrounds	[47,49,51,52]
Chronic liver disease
Viral hepatitis	Conflicting results, Female generally have higher rate of symptoms but increased viral clearance	Females display more efficient innate, humoral and cell-mediated immune response (higher cytotoxic T cells, higher CD4+/CD8+ ratio and higher CD4+ T cells), as well as more TLRs	[70,71,72,84]
ALD	1:2	Estrogen-induced activation of KCs after alcohol administration in female rats increases hepatocyte inflammation and necrosis Alcohol exposure in female decreases upregulation of hepatoprotective genes, and genes involved in compensatory pathways, inflammation and oxidative stress	[98,99,100,103,159]
NAFLD	n.a.	Higher FA clearance and synthesis in females (increased FA transport protein expression) Higher LDL-cholesterol in men and postmenopausal women E2 seems to be protective for NAFLD	[107,110,112,114,115]
PBC	1:10	Estrogen-dependent alteration of HLA expression, cytokine release and cholangiocyte proliferation	[34,120,123]
PSC	2.6:1	Few evidences suggest a correlation between a good female reproductive health and childbearing and delay of PSC development	[128,129]
AIH	1:3.5	Female hormone-related modulation of immune system improving AIH-induced inflammation	[42,72]
Benign hepatic cancerous lesions	1:5–15 (depending on types)	Estrogens improve the outcome of benign lesions	[160,161]
HCC	3–4:1	Estrogen-modulated IL6 decrease in females improves HCC progression, through regulating NRF2-antioxidant response Increased expression of TLRs involved in the innate immune response, Higher rate of CD4+ cells in females with respect to males Males better respond than female to checkpoint blockade therapy since sex hormones control PD1-PDL1 expression.	[144,145,150,151,154,155,156,157]