J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Review

Volume 9, Number 4, April 2017, pages 233-247

Insulin-Like Growth Factor-1 Deficiency and Cirrhosis Establishment

**Table 1.** Population Fractions for Liver Cirrhosis Risk Factors by Region in 2010
Region name	Alcohol	Hepatitis B	Hepatitis C	Other*
*Not attributable to chronic alcohol intake, and tested negative to anti-VHC antibodies and HbsAg. Adapted from Mokdad et al, BMC Medicine 2014;12:145.
Asia Pacific, high income	0.24	0.31	0.25	0.20
Asia, Central	0.16	0.36	0.18	0.29
Asia, East	0.18	0.39	0.18	0.26
Asia, South and Southeast	0.40	0.58	0.44	0.59
Australia	0.31	0.30	0.18	0.21
Caribbean	0.25	0.14	0.25	0.36
Europe, Central	0.27	0.15	0.22	0.36
Europe, Eastern	0.30	0.13	0.23	0.34
Europe, Western	0.33	0.11	0.30	0.27
Latin America, Andean	0.23	0.21	0.21	0.36
Latin America, Central	0.29	0.08	0.26	0.37
Latin America, Southern	0.31	0.12	0.28	0.29
Latin America, Tropical	0.31	0.06	0.27	0.37
North America, high income	0.33	0.06	0.29	0.32
North Africa, Middle East	0.14	0.27	0.24	0.36
Sub-Saharan Africa, Central	0.15	0.37	0.20	0.27
Sub-Saharan Africa, East	0.16	0.34	0.20	0.30
Sub-Saharan Africa, Southern	0.19	0.37	0.18	0.27
Sub-Saharan Africa, West	0.15	0.38	0.18	0.28
Oceania	0.13	0.44	0.17	0.26

Table 1. Population Fractions for Liver Cirrhosis Risk Factors by Region in 2010

Region name

Alcohol

Hepatitis B

Hepatitis C

Other*

*Not attributable to chronic alcohol intake, and tested negative to anti-VHC antibodies and HbsAg. Adapted from Mokdad et al, BMC Medicine 2014;12:145.

Asia Pacific, high income

0.24

0.31

0.25

0.20

Asia, Central

0.16

0.36

0.18

0.29

Asia, East

0.18

0.39

0.18

0.26

Asia, South and Southeast

0.40

0.58

0.44

0.59

Australia

0.31

0.30

0.18

0.21

Caribbean

0.25

0.14

0.25

0.36

Europe, Central

0.27

0.15

0.22

0.36

Europe, Eastern

0.30

0.13

0.23

0.34

Europe, Western

0.33

0.11

0.30

0.27

Latin America, Andean

0.23

0.21

0.36

Latin America, Central

0.29

0.08

0.26

0.37

Latin America, Southern

0.31

0.12

0.28

0.29

Latin America, Tropical

0.31

0.06

0.27

0.37

North America, high income

0.33

0.06

0.29

0.32

North Africa, Middle East

0.14

0.27

0.24

0.36

Sub-Saharan Africa, Central

0.15

0.37

0.20

0.27

Sub-Saharan Africa, East

0.16

0.34

0.20

0.30

Sub-Saharan Africa, Southern

0.19

0.37

0.18

0.27

Sub-Saharan Africa, West

0.15

0.38

0.18

0.28

Oceania

0.13

0.44

0.17

0.26

**Table 2.** Inflammatory Mediators Implicated in Hepatic Fibrogenesis
Tipo	Mediator	Target cells and mechanisms of action	Liver disease/model
Adapted from Seki et al, Hepatology, 2015.
Inflammatory cytokines	IL-1	Up-regulates TIMP-1 and down-regulates BAMBI in HSCs. Promotes HSC survival. Promotes lipid accumulation and cell death in hepatocytes during NASH and ALD.	Experimental fibrosis induced by BDL or TAA; experimental NASH by CDAA diet; experimental ALD model induced by Lieber-DeCarli and ethanol binge injection.
	IL-33	Secreted from damaged hepatocytes, stimulating ILC2 to produce IL-13 that in turn activates HSC.	Human liver cirrhosis; experimental fibrosis induced by CCl₄, TAA or Schistosoma mansonii infection.
	TNF-α	Induces apoptosis of the hepatocytes. Up-regulates TIMP-1 and down-regulates BAMBI in HSCs. Promotes HSC survival and proliferation. Activates liver macrophages.	Experimental fibrosis induced by BDL; experimental NASH model induced by MCD diet.
	IL-17	Stimulates KCs and HSC to produce IL-6, TNF-α, and TGF-β. Activates NF-kB and STAT3 in KCs and HSCs. HSCs activation through STAT3.	Hepatitis B, experimental fibrosis induced by CCl₄ or BDL.
	IL-20	Promotes activation, proliferation, and migration of HSCs. Prevents hepatocyte injury.	HBV- and HCV-induced liver cirrhosis; experimental fibrosis induced by CCl₄.
	IL-22	Induces HSC senescence through STAT3-p53. HSC senescence inhibits liver fibrosis.	HBV-, HCV- and alcohol-induced liver cirrhosis; experimental fibrosis induced by CCL₄.
	IFN-γ	Suppresses HSC proliferation and activation. Activates NK cells to promote HSC killing.	Experimental fibrosis induced CCl₄.
Chemokines	CCl₂ (MCP-1)	Macrophage and HSC recruitment; HSC activation.	Experimental fibrosis induced by CCl₄ or BDL; experimental NASH model induced by MCD or CDAA diet.
	CCL5	Macrophage and HSC recruitment; HSC activation.	Experimental fibrosis induced by CCl₄.
	CXCL9	Suppresses HSC activation. Inhibits angiogenesis that inhibits liver fibrosis.	Experimental fibrosis induced by CCl₄.
	CXCL10	Promotes hepatocyte death and HSC activation. Inhibits NK cell-mediated HSC inactivation.	Experimental fibrosis induced by CCl₄.
	CX3CL1	Prolongs KC survival. Promotes anti-inflammatory property in KCs.	Experimental fibrosis induced by CCl₄ or BDL.
Gut microbiota axis/TLR pathway	TLR4	Directly stimulates HSC to down-regulate BAMBI and produce chemokines in BDL and CCl₄-induced liver fibrosis. Stimulates KCs to produce proinflammatory and fibrogenic cytokines that activate HSCs in ALD and NASH. Stimulates LSECs to induce angiogenesis that promotes HSC activation and fibrosis.	Experimental fibrosis induced by CCl₄ or BDL; experimental NASH model induced by MCD or CDAA diet; experimental ALD model induced by Lieber-DeCarli or Tsukamoto-French model.
	TLR2	Stimulates KCs to produce cytokines that activate HSCs in NASH. Stimulates macrophages in intestine, which promote bacterial translocation.	Experimental fibrosis induced by CCl₄ or BDL; experimental NASH model induced by CDAA diet.
	TLR9	Stimulates KCs to produce cytokines that activate HSCs in NASH. Stimulates HSCs by host DNA released from apoptotic Hepatocytes.	Experimental NASH model induced by CDAA diet; experimental fibrosis induced by CCl₄ or BDL.
	TLR3	Stimulates NK cells to produce IFN-c that induces antifibrotic effect by killing HSCs.	Experimental fibrosis induced by CCl₄ or Lieber-DeCarli plus CCl₄.
	TLR7	Stimulates DCs to produce type I IFN that inhibits liver fibrosis.	Experimental fibrosis induced by CCl₄ or BDL.

Table 2. Inflammatory Mediators Implicated in Hepatic Fibrogenesis

Tipo

Mediator

Target cells and mechanisms of action

Liver disease/model

Adapted from Seki et al, Hepatology, 2015.

Inflammatory cytokines

IL-1

Up-regulates TIMP-1 and down-regulates BAMBI in HSCs.
Promotes HSC survival.
Promotes lipid accumulation and cell death in hepatocytes during NASH and ALD.

Experimental fibrosis induced by BDL or TAA; experimental NASH by CDAA diet; experimental ALD model induced by Lieber-DeCarli and ethanol binge injection.

IL-33

Secreted from damaged hepatocytes, stimulating ILC2 to produce IL-13 that in turn activates HSC.

Human liver cirrhosis; experimental fibrosis induced by CCl₄, TAA or Schistosoma mansonii infection.

TNF-α

Induces apoptosis of the hepatocytes.
Up-regulates TIMP-1 and down-regulates BAMBI in HSCs.
Promotes HSC survival and proliferation.
Activates liver macrophages.

Experimental fibrosis induced by BDL; experimental NASH model induced by MCD diet.

IL-17

Stimulates KCs and HSC to produce IL-6, TNF-α, and TGF-β.
Activates NF-kB and STAT3 in KCs and HSCs.
HSCs activation through STAT3.

Hepatitis B, experimental fibrosis induced by CCl₄ or BDL.

IL-20

Promotes activation, proliferation, and migration of HSCs.
Prevents hepatocyte injury.

HBV- and HCV-induced liver cirrhosis; experimental fibrosis induced by CCl₄.

IL-22

Induces HSC senescence through STAT3-p53.
HSC senescence inhibits liver fibrosis.

HBV-, HCV- and alcohol-induced liver cirrhosis; experimental fibrosis induced by CCL₄.

IFN-γ

Suppresses HSC proliferation and activation.
Activates NK cells to promote HSC killing.

Experimental fibrosis induced CCl₄.

Chemokines

CCl₂ (MCP-1)

Macrophage and HSC recruitment; HSC activation.

Experimental fibrosis induced by CCl₄ or BDL; experimental NASH model induced by MCD or CDAA diet.

CCL5

Macrophage and HSC recruitment; HSC activation.

Experimental fibrosis induced by CCl₄.

CXCL9

Suppresses HSC activation.
Inhibits angiogenesis that inhibits liver fibrosis.

Experimental fibrosis induced by CCl₄.

CXCL10

Promotes hepatocyte death and HSC activation.
Inhibits NK cell-mediated HSC inactivation.

Experimental fibrosis induced by CCl₄.

CX3CL1

Prolongs KC survival.
Promotes anti-inflammatory property in KCs.

Experimental fibrosis induced by CCl₄ or BDL.

Gut microbiota axis/TLR pathway

TLR4

Directly stimulates HSC to down-regulate BAMBI and produce chemokines in BDL and CCl₄-induced liver fibrosis.
Stimulates KCs to produce proinflammatory and fibrogenic cytokines that activate HSCs in ALD and NASH.
Stimulates LSECs to induce angiogenesis that promotes HSC activation and fibrosis.

Experimental fibrosis induced by CCl₄ or BDL; experimental NASH model induced by MCD or CDAA diet; experimental ALD model induced by Lieber-DeCarli or Tsukamoto-French model.

TLR2

Stimulates KCs to produce cytokines that activate HSCs in NASH.
Stimulates macrophages in intestine, which promote bacterial translocation.

Experimental fibrosis induced by CCl₄ or BDL; experimental NASH model induced by CDAA diet.

TLR9

Stimulates KCs to produce cytokines that activate HSCs in NASH.
Stimulates HSCs by host DNA released from apoptotic Hepatocytes.

Experimental NASH model induced by CDAA diet; experimental fibrosis induced by CCl₄ or BDL.

TLR3

Stimulates NK cells to produce IFN-c that induces antifibrotic effect by killing HSCs.

Experimental fibrosis induced by CCl₄ or Lieber-DeCarli plus CCl₄.

TLR7

Stimulates DCs to produce type I IFN that inhibits liver fibrosis.

Experimental fibrosis induced by CCl₄ or BDL.

**Table 3.** Factors Up- and Down-Regulated After IGF-1 Gene Transfer in Cirrotic Patients (Modified From Bonefeld and Moller, Liver Int. 2011)
Up-regulated hepatoprotective factors	Down-regulated profibrogenic factors
Same factors could be involved in the positive clinical outcome seen when supplementing with rhIGF-1.
HGF	Hepatocyte growth factor	Activated HSC	Activated hepatic stellate cells
MMPs	Matrix metalloproteases	αSMA	α-smooth muscle actin
HNF4α	Hepatocyte nuclear factor 4α	TGF-β	Transforming growth factor-β
STAT3a	Signal transducer and activator of transcription 3a	STAT3b	Signal transducer and activator of transcription 3a
Egfr	Epidermal growth factor receptor	TIM1 and TIM2	Tissue inhibitors of MMPs
Hnf6	Hepatocyte nuclear factor 6	PDGF	Platelet-derived growth factor
Prlr	Prolactin receptor	CTGF	Connective tissue growth factor
Lifr	Leukemia inhibitory factor receptor	WT-1	Wilm’s tumor 1

Table 3. Factors Up- and Down-Regulated After IGF-1 Gene Transfer in Cirrotic Patients (Modified From Bonefeld and Moller, Liver Int. 2011)

Up-regulated hepatoprotective factors

Down-regulated profibrogenic factors

Same factors could be involved in the positive clinical outcome seen when supplementing with rhIGF-1.

HGF

Hepatocyte growth factor

Activated HSC

Activated hepatic stellate cells

MMPs

Matrix metalloproteases

αSMA

α-smooth muscle actin

HNF4α

Hepatocyte nuclear factor 4α

TGF-β

Transforming growth factor-β

STAT3a

Signal transducer and activator of transcription 3a

STAT3b

Signal transducer and activator of transcription 3a

Egfr

Epidermal growth factor receptor

TIM1 and TIM2

Tissue inhibitors of MMPs

Hnf6

Hepatocyte nuclear factor 6

PDGF

Platelet-derived growth factor

Prlr

Prolactin receptor

CTGF

Connective tissue growth factor

Lifr

Leukemia inhibitory factor receptor

WT-1

Wilm’s tumor 1