Introduction
Methods
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Electronic databases 1980 – April 2009
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Cochrane Library 2009
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Reference lists from relevant articles
Inclusion/exclusion criteria
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were systematic reviews, meta-analyses or primary studies of diagnostic tests
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were written in English
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used liver biopsy as a reference standard
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presented data as sensitivity or specificity or diagnostic accuracy or receiver operator characteristic curve (ROC) analyses
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included >30 participants (as smaller studies will be underpowered to produce precise estimates of test performance and would be more likely to produce zero denominator effects in a 2 × 2 table. Confidence intervals would be very wide and inclusion in SROC where studies are unweighted may result in skewed unreliable results).
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data were extractable by cause of liver disease and by fibrosis stage.
Data extraction strategy
Study Author: Yr published (date of study when reported) Country(No. centres) | Total no patients |
Patient selection
| Alcohol consumption inclusion criteria | % cirrhosis (significant fibrosis*) | Age Yr mean (SD) | % male | Liver biopsy scoring system | Serum marker or panel |
---|---|---|---|---|---|---|---|---|
Recruitment details (where reported) | Fibrosis stages |
Length biopsy/no portal triads
| ||||||
Gabrielli 1989 [15] Italy (1) | 44 | Patients with ALD on biopsy /clinical | n/r | n/r | 52 | 84 | Local n/r | PIIINP |
Consecutive prospective recruitment | fibrosis 29% no fibrosis 15% | |||||||
Poynard 1991 [16] (1982–1987) France (1) | 624 | Patients admitted with alcoholism or diagnosed ALD | ≥ 50 g alcohol daily for last 5 years | 29 (11) | 49 | 75 | Local n/r | PGA (GGT PT Apo A1)PT |
(a) 333 training | 24% no fibrosis | |||||||
(b) 291 validation | Consecutive prospective recruitment | |||||||
Li 1994 [17] USA (1) | 44 | Patients undergoing biopsy for clinical reason. with h/o heavy alcohol | >80 g daily at least 5 years | 23 (70) | 45 (range | 100 | Local n/r | PIIINP TIMP 1 |
Prospective recruitment | Periven fibrosis 23% | 227–69) | ||||||
Oberti 1997 [18] France(1) | 160 total (a)109 compensated | Admissions for alcoholism/ diagnosed ALD | >50 g alcohol daily for 5 years with abn AST > 6 m | 59 | 65 | n/r | modified METAVIR n/r | HA |
Consecutive prospective recruitment | PT | |||||||
146 | Heavy drinkers admitted for detoxification+/−rehabilitation | >80 g alcohol daily for >5 year | 40 (51) | 49 | 73 | Local n/r | HA | |
PGA | ||||||||
YKL | ||||||||
France(1) | Consecutive prospective recruitment | Tran index | ||||||
(HA; PT; Apo A1) | ||||||||
Plevris 2000 [21] | 70 | Patients with ALD diagnosed by histology | n/r | n/r | n/r | n/r | Local n/r | HA |
Prospective recruitment | ||||||||
Croquet 2002 [22] | 240 | Patients admitted for alcoholism or ALD | 50 g daily past 5 years | 48 (74) | n/r | n/r | METAVIR | PT |
20 ± 7 mm
| ||||||||
(≥10 mm in 98% cases)
| ||||||||
France(1) | Prospective recruitment |
12 ± 5 portal tracts
| ||||||
Study Author: Yr published (date of study) country
No. centres
|
Total no patients
|
Patient selection
|
Alcohol consumption inclusion criteria
|
% cirrhosis (significant fibrosis*)
|
Age Yr mean (SD)
|
% male
|
Liver biopsy scoring system
|
Serum marker
|
Recruitment details (where reported
|
Length biopsy/no portal triads
| |||||||
Stickel 2003 [23] Germany (1) | 87 | Admissions for alcohol withdrawal symptoms in current drinkers | >100 g alcohol daily | 14 (44) | n/r | n/r | Local; Ludwig; Knodell n/r | HA |
Steatosis + mild fibrosis 23% | ||||||||
Steatosis + mod fibrosis + inflam 8% | ||||||||
Severe fib + inflam 30% | ||||||||
Rosenberg 2004 [24] (1998–2000) England (8) Germany Italy Sweden | 64 | Patients with excess alcohol consumption history and histology | Assessed by each centre | 27 | 44 | 63 | Scheuer | ELF panel |
Ishak | (HA TIMP1 PIIINP age) | |||||||
Consecutive prospective recruitment |
≥12 mm ≥5 portal tracts
| |||||||
Naveau 2005 [25] (1996–2000) France(1) | 221 | Patients with active history of excess alcohol consumption admitted to hospital (24% decompensated cirrhosis) and with available histology | >50 g alcohol daily for 1 year | 31(64) | 47 | 77 | METAVIR | Fibrotest (α2M, apoA1, bilirubin, GGT, haptogloblin, corrected for age + sex) |
Stage 0 7% | Mean length 15 mm ± 05 | |||||||
Stage 1 329% | ||||||||
Stage 2 22% | Frags = 2.2 ± 0.1 | |||||||
Prospective recruitment | Stage 3 11% | portal tr 14.4 ± 0.7 | HA | |||||
Stage 4 31% | ||||||||
Cales 2005 [26] (1994–2002) France (1) | 95 | Heavy drinkers with ALD on histology | >50 g daily >5 years | 41 (80) | 49.8 (11.2) | 71.6 | METAVIR | Fibrometer (PT α2M HA) |
Consecutive prospective recruitment | Stage 0 13% |
Median Length 18.4 ±6.0
| ||||||
Stage 1 18% | ||||||||
Stage 2 17% | ||||||||
Stage 3 12% | ||||||||
Stage 4 41% | ||||||||
Lieber 2006 [27] USA (23) | 1034: (a) 507 pre-cirrhotic (b) 527 decompensated cirrhosis | Patients with heavy alcohol consumption + fibrosis/cirrhosis on biopsy/clinical in 2 treatment RCTs | 80 g ethanol daily >5 years HCV negative | 51(66) | (a) 51 | 98 | Ishak | APRI |
(b) 56 |
n/r
| (AST Platelets) | ||||||
Prospective recruitment | ||||||||
Study Author: Yr published (date of study) country
No. centres
|
Total no patients
|
Patient selectionrecruitment details (where reported)
|
Alcohol consumption inclusion criteria
|
% cirrhosis (significant fibrosis*)
|
Age Yr mean (SD)
|
% male
|
Liver biopsy scoring system
|
Serum marker
|
Mean length mm/no portal tracts
| ||||||||
Nguyen –Khac 2008 [28] | 103 | Patients with attending hepato-GI, alcoholism & Int Med depts. who were HBV- and HCV- without decompensated cirrhosis who agreed to have liver biopsy | >50 g daily alcohol for >5 yrs | 33 (75) | 53 (9.6) | 74 | METAVIR | HA |
Stage 0 8% |
length 12.2 ±3 mm
| Hepascore | ||||||
Stage 1 18% |
Portal tracts 7.8 ± 2.7
| (bilirubin GGT HA age,sex α2M) | ||||||
Stage 2 23% | ||||||||
Stage 3 19% | PGA | |||||||
Prospective recruitment | Stage 4 32% | PGAA (PT GGT α2M, apoA1) | ||||||
APRI(AST Pl) | ||||||||
Fibrotest | ||||||||
Fibrometer | ||||||||
*(fibroscan) | ||||||||
Lieber 2008 [29] (1994–2000) | 247 | Heavy alcohol consumption and fibrosis on biopsy | ≥80 g daily . ≥5 years (~16 drinks daily for mean 19 yrs) | (45) | 50 | 98 | Worner & Lieber n/r | HA |
Mild fibrosis 55% | TIMP1 | |||||||
P3NP | ||||||||
Naveau 2009 [30] (1996–2000 same population as 2005 paper) France (1) | 218 | Heavy alcohol consumption and available liver biopsy HCV- HIV- | ≥50 g alcohol daily for1previous year | 31 (63) | 47 (0.07) | 78 | METAVIR | FT |
Stage 0 7% | Biopsy/ serum ≤1 month apart | Fibrometer (HA PT α2M) | ||||||
Retrospective | Stage 1 30% | |||||||
Stage 2 22% | Mean length 15 mm ± 05 | Hepascore (α2M GGT Bilirubin HA) | ||||||
Stage 3 10% | No frags 2.2 ± 0.1portal tr 14.4 ± 0.7 | |||||||
Stage 4 31% | Forns (age GGT cholesterol pl) | |||||||
APRI | ||||||||
FIB4 (platelets ALT AST) |
Degree of fibrosis tested | Study | No. | AUC | Cut off used | Sens | Spec | PPV | NPV | LR + (95% CI) | LR – (95% CI) |
---|---|---|---|---|---|---|---|---|---|---|
HA
| ||||||||||
Cirrhosis | Oberti [18] (1997) | 109* | n/r | 60mcg/l | 100 | 60 | 78 | 97 | 2.5 (1.7,3.6) | 0.02(0.004,0.18) |
Tran [19] (2000) | 146 | n/r | 60mcg/l | 100 | 86 | 83 | 99 | 6.8 (4.1,11.4) | 0.02 (0.004,0.1) | |
Plevris [21] (2000) | 70 | n/r | 100mcg/l | 87 | 89 | n/a | n/a | 8.0 | 0.15 | |
Stickel [23] (2003) | 87 |
0.78
| 250mcg/l | 100 | 69 | 35 | 98 | 3 (2.0, 4.28) | 0.10 (0.02,0.69) | |
Naveau [25] (2005) | 221 | 0.93 (0.91,0.95) | n/r | n/r | n/r | n/r | n/r | n/r | n/r | |
Nguyen-Khac [28] (2008) | 103 | 0.80 (0.68,0.92_ | n/r | n/r | n/r | n/r | n/r | n/r | n/r | |
Stage 012 vs34 | Stickel [23] (2003) | 87 |
0.76
| 55.5 mcg/l | 83 | 69 | 67 | 83 | 3(1.7, 4.2) | 0.26 (0.13,0.53) |
Nguyen-Khac [28] (2008) | 103 - | 0.83 (0.74-0.92) | ||||||||
Lieber [29] (2008) | 247 |
0.69
| ||||||||
F01vs 234 | Naveau [25] (2005) | 221 | 0.79 (0.76-0.82) | n/r | n/r | n/r | n/r | n/r | n/r | |
Nguyen-Khac [28] (2008) | 103 | 0.80 (0.70-0.92) | n/r | n/r | n/r | n/r | n/r | n/r | n/r | |
Degree of Fibrosis tested
|
Study
|
No.
|
AUC (95%CI)
|
Cut off used
|
Sens
|
Spec
|
PPV
|
NPV
|
LR + (95% CI)
|
LR-(95% CI)
|
F0 vs 1-4 | Nguyen-Khac [28] (2008) | 103 | 0.76 (0.58-0.94) | n/r | n/r | n/r | n/r | n/r | n/r | n/r |
P3NP
| ||||||||||
F012 vs34 | Gabrielli [15] (1989) | 44 | n/r | 16 ng/ml | 71 | 50 | n/r | n/r | 1.4 | 0.6 |
Lieber [29] (2008) | 247 |
0.67
| ||||||||
F0 vs F1-6 | Gabriella [15] (1989) | 44 | n/r | 16 ng/ml | 90 | 59 | n/r | n/r | 2 | 0.2 |
Li [17] (1994) | 44 | 0.80 ±0.07 | 1.1 U/ml | 45 | 100 | 94 | 44 | 6.8 (0.99, 47) | 0.6 (0.42, 0.82) | |
Prothrombin Index**
| ||||||||||
Cirrhosis | Oberti [18] (1997) | 109 | n/r | 85% | n/r | n/r | n/r | n/r | n/r | n/r |
Croquet [22] (2002) | 240 | n/r | 80% | 81 | 99 | 99 | 85 | 101(14.3,713.5 | 0.2 (0.13,0.28) | |
Tran [19] (2000) | 146 | n/r | 85% | 83 | 93 | 89 | 89 | 12.1(5.56,26.5) | 0.2 (0.1,0.33) | |
TIMP1
| ||||||||||
F012 vs 34(advanced fibrosis) | Lieber [29] (2008) | 247 |
0.68
| n/r | n/r | n/r | n/r | n/r | n/r | |
Any fibrosis (1994) | Li [17] | 44 | 0.96 ±0.03 | 313 ng/ml | n/r | n/r | n/r | n/r | n/r | n/r |
YKL
| ||||||||||
Cirrhosis | Tran [19] (2000) | 146 | n/r | 330mcg/l | 51 | 89 | 75 | 74 | 5 (2.4,8.6) | 0.5 (0.4,0.7) |
ApoA1
| ||||||||||
Cirrhosis | Tran [19] (2000) | 146 | n/r | 1.2 g/l | 83 | 93 | 89 | 89 | 12.1 (5.6,26.5) | 0.18 (0.10,0.33) |
Data analysis/synthesis
Results
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Not primary study (editorial/non systematic review) n = 3
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Outcome was not fibrosis (usually alcoholic hepatitis) n = 6
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Participants <30 n = 1
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No results separable for ALD alone n = 6
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No results reported as sensitivity, specificity, ROC curves, diagnostic accuracy n = 11 (Most of these studies reported correlation coefficients/differences in means of serum markers between group with fibrosis and those with less fibrosis).
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No results for fibrosis alone separable from data that combined steatosis with fibrosis or fibrosis/cirrhosis with acute alcoholic hepatitis (AH) n = 4
Fibrosis grade | Study | No. | Test | AUROCS | Cut off | Sens | Spec | PPV | NPV | LR+ | -LR |
---|---|---|---|---|---|---|---|---|---|---|---|
(95% CI) | (95% CI) | ||||||||||
Cirrhosis | Poynard [16] 1991 | 624 | PGA | n/r | 6 | 85 | 85 | 70 | 93 | 5.6 (4.5 7.01) | 0.18 (0.12,0.25) |
Cirrhosis | Tran [19] 2000 | 146 | Tran | n/r | 76 | 99 | 98 | 86 | 66.8 (9.5,471.2) | 0.24 (0.15,0.37) | |
Cirrhosis | Naveau [25] 2005 | 221 | Fibrotest |
0.95 (0.94, 0.96)
| 0.3 | 84 | 41 | 39 | 85 | 1.4 (1.2,1.7) | 0.39 (0.2,0.70) |
0.7 | 60 | 72 | 49 | 80 | 2.1 (1.6,2.9) | 0.55 (0.40,0.75) | |||||
Cirrhosis | Lieber [27] 2006 | 1034 | APRI |
0.79
| >2.0 | 17 | 86 | 56 | 50 | 1.2 (0.9,1.6) | 1.0 (0.92,1.02) |
Cirrhosis | Nguyen –Khac [28] 2008 | 103 | Fibrotest |
0.84 (0.72,0.97)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r |
Fibrometer |
0.85 (0.74,0.96)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
Hepascore |
0.76 (0.63,0.90)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
APRI |
0.56 (0.38,0.73)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
PGA |
0.89 (0.82 0.97)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
PGAA |
0.83 (0.73-0.93)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
Cirrhosis | Naveau [30] 2009 | 218 | Fibrotest |
0.94 (0.90,0.96)
| 0.56 | 90 | n/r | n/r | n/r | n/r | n/r |
0.78 | n/r | 90 | n/r | n/r | n/r | n/r | |||||
>0.30 | 100 | 50 | 47 | 100 | 2.0 | 0.50 | |||||
>0.70 | 87 | 86 | 73 | 94 | 6.2 | 0.16 | |||||
Fibrometer |
0.94 (0.90,0.97)
| 0.92 | 90 | n/r | n/r | n/r | n/r | n/r | |||
0.997 | n/r | 90 | n/r | n/r | n/r | n/r | |||||
>0.50 | 99 | 62 | 54 | 99 | 2.6 | 0.38 | |||||
>1.0 | 88 | 88 | 76 | 94 | 7.3 | 0.14 | |||||
Hepascore |
0.92 (0.87,0.97)
| 0.97 | 90 | n/r | n/r | n/r | n/r | n/r | |||
0.99 | n/r | 90 | n/r | n/r | n/r | n/r | |||||
Forns |
0.38 (0.27,0.47)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
APRI |
0.67 (0.59,0.75)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
FIB4 |
0.80 (0.72,0.86)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
F012vs 34 Severe | Rosenberg [24] 2004 | 64 | ELF |
0.94 (0.84, 1.00)
| 0.087 | 100 | 17 | 75 | 100 | 1.2 (1.1, 1.4) | 0.06 (0.01, 0.3) |
0.431 | 93 | 100 | 100 | 86 | 68 (37,124) | 0.08 (0.05,0.1) | |||||
F012vs 34 Severe | Nguyen –Khac [28] 2008 | 103 | FT |
0.80 (0.7,0.9)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r |
Fibrometer |
0.88 (0.8,0.95)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
Hepascore |
0.83 (0.74,0.93)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
APRI |
0.43 (0.30,0.56)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
PGA |
0.84 (0.74 0.94)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
F012vs 34 Severe | Lieber [29] 2008 | 247 | HA | n/r | n/r | 76 | 68 | 53 | 86 | 2.4 | 0.35 |
P3NP | |||||||||||
TIMP1 | |||||||||||
Age | |||||||||||
As panel | |||||||||||
F01 vs 2-4 Mod/severe | Cales [26] 2005 | 95 | Fibrometer |
0.96 (0.94, 0.98)
| n/r | 92 | 93 | 99 | 76 | 18 (2.7,125) | 0.08 (0.2) |
F01vs 2-4 Mod-severe | Naveau [22] 2005 | 221 | Fibrotest |
0.84 (0.81 0.87)
| 0.3 | 84 | 66 | 81 | 70 | 2.5 (1.8,3.4) | 0.25 (0.16,0.40) |
0.7 | 55 | 93 | 93 | 54 | 7.4 (3.3,16.1) | 0.5 (0.4,0.6) | |||||
F01vs2-4 Mod severe | Lieber [27] 2006 | 507 | APRI |
0.70
| 0.2 | 94 | 26 | 71 | 68 | 1.3 (1.2,1.4) | 0.24 (0.17,0.33) |
0.6 | 47 | 82 | 84 | 44 | 2.6 (2.0,3.3) | 0.65 (0.6,0.71) | |||||
1.0 | 21 | 90 | 80 | 37 | 2.1 (1.5, 3.0) | 0.88 (0.83,0.92) | |||||
1.6 | 13 | 95 | 83 | 36 | 2.5 (1.5,4.1) | 0.92 (0.88,0.95) | |||||
2.0 | 9 | 97 | 86 | 35 | 3.1 (1.6,6.1) | 0.94 (0.91,0.96) | |||||
F01vs2-4 Mod severe | Nguyen –Khac [28] 2008 | 103 | Fibrotest |
0.79 (0.69,0.90)
| n/r | n/r | n/r | n/r | n/r | n/r | |
Fibrometer |
0.82 (0.72,0.93)
| n/r | n/r | n/r | n/r | n/r | n/r | ||||
Hepascore |
0.76 (0.64,0.88)
| n/r | n/r | n/r | n/r | n/r | n/r | ||||
APRI |
0.54 (0.4-0.68)
| n/r | n/r | n/r | n/r | n/r | n/r | ||||
PGA |
0.78 (0.68,0.89)
| n/r | n/r | n/r | n/r | n/r | n/r | ||||
PGAA |
0.81 (0.71,0.91)
| n/r | n/r | n/r | n/r | n/r | n/r | ||||
F01vs2-4 Mod severe | Naveau [30] 2009 | 218 | Fibrotest |
0.83 (0.77,0.88)
| 0.23 | 90 | n/r | n/r | n/r | n/r | n/r |
0.64 | n/r | 90 | n/r | n/r | n/r | n/r | |||||
>0.30 | 88 | 52 | 76 | 72 | 1.8 | 0.55 | |||||
>0.70 | 43 | 97 | 96 | 50 | 14.3 | 0.07 | |||||
Fibrometer |
0.83 (0.77,0.87)
| 0.11 | 90 | n/r | n/r | n/r | n/r | n/r | |||
0.95 | n/r | 90 | n/r | n/r | n/r | n/r | |||||
>0.50 | 74 | 74 | 83 | 62 | 2.85 | 0.35 | |||||
1.0 | 55 | 95 | 95 | 55 | 11.0 | 0.09 | |||||
Hepascore |
0.83 (0.77,0.88)
| 0.25 | 90 | n/r | n/r | n/r | n/r | n/r | |||
0.94 | n/r | 90 | n/r | n/r | n/r | n/r | |||||
Forns |
0.38 (0.30,0.46)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
APRI |
0.59 (0.51,0.67)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
FIB4 |
0.70 (0.62,0.76)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r | |||
Mild fibrosis | Lieber [29] 2008 | 247 | HA | n/r | n/r | 74 | 76 | 86 | 53 | 3.1 | 0.34 |
P3NP | |||||||||||
TIMP1 | |||||||||||
Age | |||||||||||
As panel test | |||||||||||
Any fibrosis | Nguyen –Khac [28] 2008 | 103 | Fibrotest |
0.77 (0.63,0.90)
| n/r | n/r | n/r | n/r | n/r | n/r | n/r |
Fibrometer |
0.72 (0.57,0.87)
| ||||||||||
Hepascore |
0.70 (0.51,0.89)
| ||||||||||
APRI |
0.76 (0.58,0.95)
| ||||||||||
PGA |
0.66 (0.50,0.82)
| ||||||||||
PGAA |
0.74 (0.60,0.88)
|