Iron and liver fibrosis: Mechanistic and clinical aspects

Table 1 Iron-related characteristics and components of transforming growth factor-β pathway and bone morphogenetic protein signalling

Stimulant	Pathway	Type II receptors	Type I receptors	Receptor-SMADs phosphorylated	Common SMAD	Significance/feature of pathway
BMPs (Belong to TGF-β superfamily)	Canonical	BMPR2, ACVR2A, ACVR2B	ALK 1,2,3,6	SMAD-1/5/8	SMAD-4	Growth, differentiation, and developmental processes
	BMP-6 induced by iron-loading (Liver specific)[133]	BMPR2, ACVR2A	ALK-2/3	SMAD-1/5/8	SMAD-4	Iron-dependent hepcidin induction, modulated by HJV, HFE and TFR2[44]
TGF-β	Canonical	TGF-β-RII	ALK-5 (TGF-β-RI)	SMAD-2/3 (Stimulation is stable over time)[44]	SMAD-4	Growth, differentiation, developmental processes and fibrotic responses.
	Non-canonical TGF-β1 induced by iron-loading[29]	TGF-β-RII	ALK-5 (TGF-β-RI)	SMAD-1/5/8 (Transient stimulation, independent of cell type)[44]	SMAD-4	Hepcidin induction, independent of modulation by HJV, HFE and TFR2[44] and independent of BMP6-mediated activation of hepcidin
Activins (Belong to TGF-β superfamily)	Canonical[134]	ACVR2A, ACVR2B	ALK-4/7	SMAD-2/3	SMAD-4	Differentiation, proliferation and determine functions of several cell types
	Non-canonical Activin B induced by inflammation[134]	ACVR2A, ACVR2B	ALK-2/3 with HJV as co-receptor	SMAD-1/5/8	SMAD-4	Hepcidin induction during inflammation[135]

ACVR: Activin receptor; ALK: Activin receptor-like kinase; BMP: Bone morphogenetic protein; BMPR: Bone morphogenetic protein receptor; HFE: High iron protein; HJV: Hemojuvelin protein; SMAD: Small mothers against decapentaplegic protein; TFR: Transferrin receptor; TFR: Transferrin receptor; TGF-β: Transforming growth factor beta; TGF-β-R: Transforming growth factor beta receptor.

Table 2 Iron-related parameters in various fibrosis-promoting chronic liver diseases

	Normal	Hereditary hemochromatosis	ALD	NAFLD/NASH	Viral hepatitis	Diabetes
Iron level/accumulation	In body: 3-5 g[7]; In RBCs: about 2.5 g; In liver: 300 mg to 1 g[7]	Can be severe; Gradual increase, can reach up to 25-30 g in liver[7]	Moderate	Mild-moderate	Mild-moderate	Mild-moderate
Serum ferritin	24-300 µg/L[109]; 15-200 µg/L[101]; < 300 ng/mL in men, < 200 ng/mL in women[2]	Mostly high, but can be normal[101]	High[69,136]	High[104,105] but 1st/3rd NASH patients can be iron deficient[86]	High[116,137]	High[138], associated with pre-diabetes
Serum hepcidin	0.4-23.3 nmol/L[139]	Low[64]	Low[69,71,140]	High[80,141]; Can be low in iron deficiency[86]; High in obesity, but not in NAFLD[142]; High in obesity with NAFLD[143]; Alterations can occur without iron-overload[111]	Low in hepatitis C infections[144]; High in hepatitis B infections without cirrhosis and normal in those with cirrhosis[145]	No major alteration in type 1[146]; Low in type 2 diabetes[147,148]
Transferrin saturation	20%-45%[101]	> 45%[101,109]	High[69,136]	Slightly raised, but can be normal or sub-normal[7]	Mostly raised[88,149], but occasionally may not statistically differ from the norm[150]	Low[138], associated with pre-diabetes

Approximate values and percentages for adults have been shown. These include ranges for both genders. ALD: Alcoholic liver disease; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; RBCs: Red blood cells.