Molecular prognostic prediction in liver cirrhosis

Table 1 Clinical prognostic system in cirrhotic patients

Outcome	Risk score	Outcome assessed	Etiology of liver disease	Proportion of cirrhotics	Variables	Note	Ref.
Death	MELD	3-mo mortality	Multiple	100%	Creatinine, bilirubin and INR	Used by UNOS for liver allocation	[34]
	MELD-Na	3 and 6-mo mortality	HCV (25%)Chronic cholestasis (23%)Autoimmune hepatitis (14%)Alcohol (13%)Cryptogenic (12%)Other (13%)	100%	Components of MELD score and serum sodium		[90]
	CTP	Mortality	Alcohol (53%)Hepatitis (23%)Cryptogenic (15%)Biliary (9%)	100%	Bilirubin, albumin, encephalopathy, ascites and prothrombin time/INR		[91,92]
	Prognostic Index	5-yr mortality	Alcohol (64%)Viral (24%)Other (12%)	100%	Albumin, INR and creatinine		[93]
	HCV risk score	5-yr mortality	HCV	87%	Age, platelets, sex		[94]
	Bell et al	Mortality	Alcohol (100%)	100%	Age, alcohol abuse and alkaline phosphatase		[95]
	HVPG	Mortality	Alcohol (44%)HCV (36%)HBV (9%)Other (11%)	100%	HVPG		[96]
	Liver stiffness measurement	Composite outcome: death, liver transplantation, variceal bleeding and ascites	Alcohol (51%)HCV (20%)NASH (8%)HBV (3%)Other (18%)	100%	Liver stiffness measurement		[97]
	Non-invasive assessment of fibrosis: FibroTest, FIB-4, APRI	Overall survival	HCV (90%)HCV-HIV (10%)	18%	Fibrotest (Alpha-2-macroglobulin, Haptoglobin, Apolipoprotein A1, GGT, bilirubin, ALT)FIB-4 (AST, ALT, platelets, age)APRI (AST, platelets)		[98]
	FIB-4	Survival in cirrhotic Child-Pugh class A subjects with HCC	HCV (70%)HBV (16%)Other (14%)	100%	FIB-4 (AST, ALT, platelets, age)	Only predictive in subjects with Child-Pugh score of 5	[99]
	Collagen proportionate area	Liver decompensation	Alcohol (38%)HCV (28%)HBV (9%)NASH (9%)Other (17%)	100%	Measuring collagen proportionate area on liver histology		[47]
HCC	ADRESS-HCC	1-yr HCC risk	HCV (46%)Alcohol (18%)NASH (18%)HBV (3%)Other (15%)	100%	Age, diabetes, race, etiology of cirrhosis, sex, and severity of liver dysfunction (Child-Pugh score)		[100]
	Velazquez et al	4-yr HCC risk	Alcohol (59%)HCV (29%)HBV (7.5%)Other (3%)	100%	Age, anti-HCV positive, prothrombin time and platelet count		[101]
	UM regression model	3 and 5-yr HCC risk	HCV (47%)Cryptogenic (19%)Alcohol (15%)Other (19%)	100%	AFP and gender	A machine-learning algorithm was also derived using 23 variables	[51]
	GAG-HCC	5 and 10-yr HCC risk	HBV	15%	Age, gender, HBV DNA, core promoter mutations, cirrhosis		[102]
	CU-HCC	5-yr HCC risk	HBV	38%	Age, albumin, bilirubin, HBV DNA, and cirrhosis		[103]
	LSM-HCC	3 and 5-yr HCC risk	HBV	31%	Liver stiffness, age, albumin, HBV DNA		[104]
	REACH-B	3, 5 and 10-yr HCC risk	HBV	0% discovery cohort, 18% validation cohort	Sex, age, ALT, HBeAg status, and serum HBV DNA level		[105]
	Risk index	Incidence of HCC	HCV after SVR	10%	Age, AST, platelet count		[106]
	scoreHCC	Incidence of HCC	HCV after SVR	30%	Age, AFP level, low platelets and advanced fibrosis		[107]
	Chang et al	5-yr HCC risk	HCV after therapy	45% fibrosis stage 3-4	Age, male sex, AFP level, low platelet, advanced fibrosis, HCV genotype 1b and non SVR		[108]
	El-Serag et al	Incidence of HCC	HCV	100%	AFP, ALT, platelets, interaction terms, and age		[50]
	HALT-C model	5-yr HCC risk	HCV	41%	Age, race, Alkaline phosphatase, esophageal varices, ever smoked, and platelet count		[109]
	REVEAL-HCV	5-yr HCC risk	HCV	4%	Age, ALT, AST/ALT ratio, HCV RNA, cirrhosis and HCV genotype		[110]
	Liver stiffness measurement	5-yr HCC risk	HBV	50%	Liver stiffness measurement		[111]
	FIB-4	Incidence of HCC	HBV	10%	FIB-4 (AST, ALT, platelets, age)		[112]

HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; MELD: Model for end-stage liver disease; MELD-Na: Model for end-stage liver disease-sodium.

Table 2 Molecular prognostic systems in cirrhotic patients

Molecular method	Risk score	Liver disease etiology	Outcomes	Sample	Proportion cirrhosis	Molecular marker	Risk groups and proportion of subjects	Note	Ref.
Gene expression	186-gene signature	HCV	Overall death,Progression to advanced cirrhosis,HCC	FFPE liver needle biopsy	100%	186-gene signature	Poor (25%)Intermediate (47%)Good prognosis (28%)		[52,53]
	HIR gene signature65-gene signature	HBV (89%)	223-gene sig: late HCC recurrence, 65-gene sig: early HCC recurrence	Frozen hepatic tissue	78%	223 (HIR) & 65-gene signature	HIR signature:High risk (32%)Low risk (68%)		[60]
	Activated HSC signature	HBV (92%)	HCC recurrence and survival	Frozen hepatic tissue	87%	37-gene signature	High risk (53%)Low risk (47%)		[62]
SNP	EGF	HCV	6-yr HCC risk	Blood	39%	EGF 61*G (rs4444903)	When combined with clinical markers:High risk (14%)Intermediate risk (29%)Low risk (57%)	Improved model when added clinical data: age, gender, smoking status, alkaline phosphatase level, platelet count	[67]
	Cirrhosis risk score	HCV	Fibrosis progression after liver transplantation	Blood	41% progressed to at least F3 fibrosis	7-SNP signature	High risk (44%)Intermediate risk (29%)Low risk (24%)		[64]
	PNPLA3	Alcohol (52%)HCV (48%)	6-yr HCC risk	Blood	100%	PNPLA3 444*G (rs738409)	When combined with clinical markers (alcoholic cirrhosis):High risk (25%)Intermediate risk (55%)Low risk (20%)		[113]
	MPO	HCV	HCC risk	Blood	100%	MPO -463*G (rs2333227)	High risk (GG, 51%)Intermediate risk (AG, 35%)Low risk (AA, 14%)		[69]
	CAT	HCV	HCC risk	Blood	100%	CAT -262*C (rs1001179)	High risk (CC, 68%)Intermediate risk (CT, 28%)Low risk (TT, 4%)	Not yet implemented in risk score	[69]
	HFE	Alcohol (54%)HCV (46%)	HCC risk	Blood	100%	HFE C282Y (rs1800562)	In alcoholic cirrhosis:High risk (GA, 8%)Low risk (GG, 92%)	Not predictive in HCV cirrhosis in this study	[114]

FFPE: Formalin fixed paraffin embedded; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; HIR: Hepatic injury and regeneration; HSC: Hepatic stellate cell; SNP: Single nucleotide polymorphism.