Non-invasive assessment of liver fibrosis in chronic liver diseases: Implementation in clinical practice and decisional algorithms

Table 1 METAVIR and Ishak staging systems for liver fibrosis

Description	METAVIR (F)	Ishak (S)
No fibrosis	0	0
Portal fibrosis without septa	1	1-2
Portal fibrosis with few septa	2	3
Septal fibrosis without cirrhosis	3	4
Cirrhosis	4	5-6

Portal fibrosis is a stellate enlargement of portal tracts without any bridging fibrosis on the biopsy sample. Few septa means at least one fibrous septum on the core biopsy. Theoretically, a fibrous septum is a bridge of connective tissue between two portal tracts, a portal tract and a centrolobular vein, or between two centrolobular veins. Septal fibrosis means that the liver biopsy is crossed by several septa; the transition between F2 and F3 by METAVIR or S3 and S4 by Ishak begins when there are more fibrous septa than portal tracts without septa on the biopsy. Cirrhosis means that liver tissue is mutilated by nodular fibrosis that delineates hepatocytes nodules.

Table 2 Pros and Cons of liver biopsy in staging of hepatic fibrosis

PROS	CONS
Staging of liver fibrosis	Invasiveness (pain, bleeding)
Grade of necroinflammation	Cost (hospitalization)
Steatosis (common in hepatitis C)	Sampling errors
Iron overload (common in hepatitis C)	Possibly refused by patient, concern of physician
Comorbidities (autoimmunity stigmates)	Static data, no information on fibrogenesis

Table 3 Features of an adequate liver biopsy sample

Length (mm)	Portal tracts (n°)	Ref.
15	5	[2829]
20	11	[30]
25	NA	[31]
Bigger is better	NA	[32]

NA: Not available.

Table 4 Features of the ideal non-invasive method for liver fibrosis

Reliable (high diagnostic accuracy)

Widely available (simple, least expensive)

Providing information on both fibrosis stage and fibrogenesis activity

Validated by large-scale studies

Validated by independent studies (different authors from the proposing study)

Validated in various etiologies of CLDs (HCV, HBV, ALD, NAFLD)

Identifying clinically important fibrosis stages (significant fibrosis and cirrhosis)

CLDs: Chronic liver diseases; ALD: Alcoholic liver disease; NAFLD: Non-alcoholic fatty liver disease.

Table 5 Single serum non-invasive markers for liver fibrosis

Direct markers	Indirect markers
Hyaluronic acid	Platelet count
Laminin	AST, ALT
Procollagen III	γGT
Type IV Collagen	γ-globulins
Metalloproteinases	Albumin
Inhibitors of metalloproteinases	Prothrombin time

Table 6 Combinations of serum parameters for non-invasive diagnosis of liver fibrosis

Marker	Description	Settings in which validation exists	Ref.
AST/ALT	AST to ALT ratio	HCV, HBV	[6364657172]
APRI	AST to platelets ratio index	HCV, HBV, HIV/HCV	[64–7275–80]
Forns’ index	Age, BMI, γGT, cholesterol	HCV, HBV, HIV/HCV	[67697275]
Fibrotest	Age, gender, α-2-macroglobulin, γGT, haptoglobin, apolipoprotein A1, total bilirubin	HCV, HBV, ALD, NAFLD, HIV/HCV	[6567727680]
ELF	Age, hyaluronic acid, type III procollagen, TIMP1	HCV, ALD, NAFLD	[6062]
Hepascore	Bilirubin, γGT, hyaluronic acid, α-2-macroglobulin, age, sex	HCV	[5859]
Lok index	AST, ALT, platelets, INR	HCV	[68]
Fibroindex	AST, platelets, g-globulins	HCV	[7172]
Fibrometer	Age, AST, platelets, hyaluronan, INR, α-2-macroglobulin, urea	HCV	[5556]
Fibrospect	α-2-macroglobulin, hyaluronan, TIMP1	HCV	[57]
Fib-4	Age, AST, ALT, platelets	HCV, HBV, HIV/HCV	[73–75]

APRI: AST-to platelet ratio index; ELF: European liver fibrosis study group.

Table 7 Performance of several serum non-invasive markers for liver fibrosis (single or combination) as expressed as AUROC

Serum marker	Significant fibrosis	Cirrhosis	Ref.
Hyaluronic acid	0.73-0.92	0.85-0.97	[40–47]
Laminin	0.82	NA	[4849]
Type IV collagen	0.83	NA	[51–53]
MMP-2	0.59	0.97	[54]
TIMP-1	0.71	0.90	[54]
ELF	0.77-0.94	NA	[60–62]
AAR	NA	0.51-0.83	[63–657172]
Forns’ index	0.75-0.86	NA	[67687072]
APRI	0.69-0.88	0.61-0.94	[1564–677276–80]
Fibrotest	0.74-0.87	0.71-0.87	[1565677276–80]
Fibroindex	0.74-0.83	NA	[7172]
Fibrometer	0.89-0.96	NA	[5556]
Fibrospect	0.83	NA	[57]
Fib-4	0.79-0.85	0.80-0.91	[73–75]
Hepascore	0.82-0.85	0.90-0.94	[5859]

AUROC: Area under the receiving operating characteristic curve; MMP-2: Metalloproteinase 2; TIMP-1: Tissue inhibitor of metalloproteinases 1; ELF: European liver fibrosis study group; AAR: AST-to-ALT ratio; APRI: AST-to-platelet ratio index.

Table 8 Accuracy of fibroscan for the diagnosis of significant fibrosis and cirrhosis

Ref.	Etiology	Accuracy for ≥ F2	Accuracy for F4
[81]	HCV	88	99
[83]	HCV	83	95
[84]	HCV	79	95
[86]	HCV	80	96
[87]	HCV	NA	95
[88]	HBV	87	88
[89]	HBV	90	94

Table 9 Limitations of fibroscan in clinical practice

Difficult to perform in obese patients (5% rate failure)

Inter-observer and intra-observer variability influenced by liver steatosis

Influence of ALT flares (HBV reactivation)

Lower performance for diagnosis of significant fibrosis

Table 10 Main features of SAFE biopsy[6794] for significant fibrosis and cirrhosis in 2035 HCV cases

	Significant fibrosis	Cirrhosis
Sensitivity (%)	100	92.7
Specificity (%)	77	90.4
Accuracy (%)	90	93
AUROC	0.9	0.92
Saved biopsies (%)	47	82

SAFE: Sequential algorithms for fibrosis evaluation; AUROC: Area under the receiving operating characteristic curve.

Table 11 Comparison of the performance of SAFE biopsy[6794], Fibropaca algorithm[96] and Leroy algorithm[97]. Results are expressed as percentages

	SAFE biopsy for diagnosis of		Fibropaca algorithm for diagnosis of		Leroy algorithm for diagnosis of ≥ F2
	≥ F2	F4	≥ F2	F4
APRI needed	100	100	100	100	100
Forns needed	0	0	100	0	0
Fibrotest needed	41.7	57.6	100	100	100
Sensitivity	100	81.8	85.5	72.7	89.6
Specificity	78.2	92.4	89.9	96.7	97.8
Accuracy	90	91.2	87.6	94	93.5
Saved biopsies	43.8	79.1	51.7	76.2	29.2

≥ F2: Significant fibrosis; F4: Cirrhosis; APRI: AST-to-platelet ratio index.

Table 12 Comparison of the performance of Bordeaux algorithm[98] and SAFE biopsy[6794]. Values are expressed as percentages

	Bordeaux algorithm		SAFE biopsy
	≥ F2	F4	≥ F2	F4
APRI needed	0	0	100	100
Fibrotest needed	100	100	43.7	61.9
Fibroscan needed	100	100	0	0
Accuracy	91	93	94	87
Biopsies saved	71.9	78.8	48.3	74.8