Type I insulin-like growth factor as a liver reserve assessment tool in hepatocellular carcinoma

Figures & data

Figure 1 Insulin-like growth factor-I (IGF-I) axis and variable sources of IGF-I production.

Abbreviations: IGFBP, insulin-like growth factor binding protein; IGF-IR, IGF-I receptor; IGF-IIR, IGF-II receptor.

Figure 2 Roles and regulations of IGF-I in relation to GH in both normal and reduced hepatic reserve.

Abbreviations: CLD, chronic liver disease; GH, growth hormone; HCC, hepatocellular carcinoma; IGF-I, insulin-like growth factor-I; GHR, GH receptor; IGFBP, IGF binding protein; IGFR, IGF receptor.

Figure 3 Roles of insulin-like growth factor-I (IGF-I) in cancer development.

Abbreviations: IGFBP, IGF binding protein; IGF-IR, IGF-I receptor; MMP-9, matrix metallopeptidase-9; uPAR, urokinase plasminogen activator receptor; ERK, extracellular signal-regulated kinases; ECM, extracellular matrix; SOS, son of sevenless; GRB2, Growth factor receptor-bound protein 2; SHC, src homology/α-collagen related protein; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

Table 1 Clinical studies of circulating IGF-I in CLDs

Study	Year	Country	Type of disease	Study design	Sample size	Correlation with liver dysfunction	Results
Kaseb et al^Citation136,Citation137	2011	USA	CLDs	Prospective cohort	288 cases	+	↓ IGF-I
Rehem and El-Shikh^Citation115	2011	Egypt	and HCC	Case-control	20 HCC 60 liver cirrhosis 20 controls	+	↓ IGF-I
Su et al^Citation139	2010	Taiwan		Case-control	65 cases 165 controls	+	↓ IGF-I (P<0.001)
Lorenzo-Zúñiga et al^Citation112	2007	Spain		Cohort	40 HCV	+	↓ IGF-I
Elsammak et al^Citation110	2006	Egypt		Case-control	30 HCC 30 HCV without chronic SHF 30 HCV with chronic SHF 30 controls	+	↓ IGF-I (P<0.001)
Stuver et al^Citation138	2000	USA		Case-control	73 HCC 25 liver metastases 111 controls	+	Serum IGF-I (P<0.0001)
Arturi et al^Citation101	2011	Italy	Steatosis and NASH	Case-control	308 nondiabetic cases 195 nondiabetic controls	+	↓ IGF-I (P=0.001)
Völzke et al^Citation102	2009	Germany		Cohort	3,863 cases	+	↓ IGF-I
Ronsoni et al^Citation116	2013	Brazil	Cirrhosis	Cross-sectional	74 cases	+	↓ IGF-I
Castro et al^Citation107	2013	Brazil		Case-control	25 cases 7 controls	+	↓ IGF-I (P<0.05)
Dehghani et al^Citation108	2012	Iran		Case-control	45 cases 38 controls	+	↓ IGF-I
Sandahl et al^Citation117	2011	Denmark		Case-control	8 cases 8 controls	+	↓ IGF-I
Jeyaratnaganthan et al^Citation111	2010	Denmark		Case-control	43 cases 11 controls	+	↓ IGF-I (P<0.05)
Assy et al^Citation105	2008	Israel		Case-control	53 cases 10 controls	+	↓ IGF-I
Wu et al^Citation119	2004	People’s Republic of China		Case-control	44 cases 38 controls	+	↓ IGF-I
Vyzantiadis et al^Citation118	2003	Greece		Case-control	40 cases 20 controls	+	↓ IGF-I
Mazziotti et al^Citation113	2002	Italy		Prospective cohort	114 HCV cases	+	↓ IGF-I in patients developed HCC
Donaghy et al^Citation109	2002	UK		Cohort	50 cases	+	↓ IGF-I/GH
Assy et al^Citation104	1998	Israel		Cohort	15 cases	+	↓ IGF-I and ↑ after rhGH
Caregaro et al^Citation106	1997	Italy		Cohort	64 cases	+	↓ IGF-I (P<0.01)
Møller et al^Citation114	1993	Denmark		Case-control	36 cases 34 controls	+	↓ IGF-I

Abbreviations: CLDs, chronic liver diseases; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis; SHF, schistosomal hepatic fibrosis; IGF, insulin-like growth factor; GH, growth hormone; rhGH, recombinant human growth hormone.

Figure 4 Kaplan–Meier curves for IGF classification of Child–Turcotte–Pugh (CTP) class A hepatocellular carcinoma patients.

Notes: (A) Training cohort (n=310). (B) Validation cohort (n=155). The first letter for each group represents the CTP class; the second letter, the IGF-CTP class (eg, group AB represents patients classified as CTP class A and IGF-CTP class B).
Abbreviation: IGF, insulin-like growth factor.

Table 2 Original CTP scoring system replaced by the new IGF-I CTP scoring system

Parameter	Original CTP score			IGF-CTP score
	1	2	3	1	2	3
Encephalopathy	None	Mild (1–2)	Severe (3–4)	–	–	–
Ascites	None	Mild/moderate	Severe/refractory	–	–	–
Albumin (g/dL)	>3.5	2.8–3.5	<2.8	Same as CTP score
PT prolongation (seconds)	<4	4–6	>6	Same as CTP score
Bilirubin (mg/dL)	<2	2–3	>3	Same as CTP score
IGF-I (ng/mL)				>50	26–50	<26

Note: Data adapted with permission, from: Kaseb AO, Xiao L, Hassan MM, et al. Development and validation of insulin-like growth factor-1 score to assess hepatic reserve in hepatocellular carcinoma. J Natl Cancer Inst. 2014;106(5). Copyright © 2014 Kaseb et al. Published by Oxford University Press.¹⁴³

Abbreviations: CTP, Child–Turcotte–Pugh; IGF, insulin-like growth factor; PT, prothrombin time.

Table 3 Ranking of scoring systems by C-index

Patient cohort	Scoring system	C-index (95% CI)	P-value
Training cohort, N=310	IGF-CTP	0.608 (0.606–0.610)	0.003
	CTP	0.573 (0.571–0.575)
First validation cohort, N=155	IGF-CTP	0.672 (0.666–0.677)	0.005
	CTP	0.579 (0.576–0.583)

Note: Data adapted with permission, from: Kaseb AO, Xiao L, Hassan MM, et al. Development and validation of insulin-like growth factor-1 score to assess hepatic reserve in hepatocellular carcinoma. J Natl Cancer Inst. 2014;106(5). Copyright © 2014 Kaseb et al. Published by Oxford University Press.¹⁴³

Abbreviations: CI, confidence interval; CTP, Child–Turcotte–Pugh; IGF, insulin-like growth factor; N, number.

Table 4 Rearrangement of originally CTP class A according to the IGF-CTP score

Originally CTP-A	Training cohort				Validation cohort
	N	%	Median OS, months (95% CI)	P-value	N	%	Median OS, months (95% CI)	P-value
IGF-CTP-A	158	72.1	19.3 (14.9–27)	<0.001	67	53.2	25.9 (18.4–NA)	<0.001
IGF-CTP-B	58	26.5	13.6 (9.1–19.7)		58	46	11 (7.7–16.9)
IGF-CTP-C	3	1.4	2.3 (1.5–NA)		1	0.8	1.2 (NA–NA)
			HR (95% CI)	P-value			HR (95% CI)	P-value
AAa			1.00 (reference)				1.00 (reference)
ABa			1.45 (1.03–2.04)	0.03			2.83 (1.65–4.85)	<0.001
ACa			1.45 (1.03–2.04)	0.02			NA	NA

Note: Data adapted with permission, from: Kaseb AO, Xiao L, Hassan MM, et al. Development and validation of insulin-like growth factor-1 score to assess hepatic reserve in hepatocellular carcinoma. J Natl Cancer Inst. 2014;106(5). Copyright © 2014 Kaseb et al. Published by Oxford University Press.¹⁴³

a The first letter for each group represents the CTP class; the second letter, the IGF-CTP class (eg, group AB represents patients classified as CTP class A and IGF-CTP class B).

Abbreviations: CI, confidence interval; CTP, Child–Turcotte–Pugh; HR, hazard ratio; IGF, insulin-like growth factor; N, number; NA, not applicable; OS, overall survival.

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