FIB-4 First in the Diagnostic Algorithm of Metabolic-Dysfunction-Associated Fatty Liver Disease in the Era of the Global Metabodemic
Abstract
:1. Introduction
2. Which Fibrosis Stage Should We Pick up in MAFLD?
Index | Formula | Strengths | Weaknesses |
---|---|---|---|
FIB-4 index [15,16] | (age [years] × AST [U/L]/(platelet count [109/L] × √ALT [U/L]) https://www.eapharma.co.jp/medicalexpert/product/livact/fib-4/calculator.html (accessed on 25 January 2021) |
|
|
NAFLD fibrosis score [26] | −1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × impaired fasting glucose/diabetes (yes = 1, no = 0) + 0.99 × AST/ALT ratio–0.013 × platelet count (×109/L) − 0.66 × albumin (g/dL) http://nafldscore.com/ (accessed on 25 January 2021) |
|
|
APRI [27] | AST to platelet ratio index |
|
|
BARD [28] | BMI > 28 kg/m2 = 1 point AST/ALT ratio > 0.8 = 2 points Diabetes = 1 point |
|
|
CA-fibrosis index [29] | 1.5 × type IV collagen 7S (ng/mL) + 0.0264 × AST (IU/l) |
|
|
ELF test [22] | −7.412 + (In [HA] × 0.681) + (In [P3NP] × 0.775) + (In [TIMP1] × 0.494) |
|
|
3. The Usefulness of FIB-4 Index to Evaluating Severe Fibrosis in MAFLD
4. The Compassion between FIB-4 Index and VCTE
5. FIB-4 Index and Carcinogenesis
6. FIB-4 Index and Mortality
7. FIB-4 Index and Risk of Cardiovascular Disease
8. FIB-4 Index and Risk of Chronic Kidney Disease
9. Distribution of FIB-4 Index in MAFLD Population
10. Drawbacks of FIB-4 Index
11. Two-Step Diagnostic Algorithm Using FIB-4 Index as the First Step
12. FIB-4 Index as Milestones of Treatment in MAFLD
13. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AASLD | American Association for the Study of Liver Diseases |
AF | atrial fibrillation |
AFP | α-Fetoprotein |
AFP-L3 | lens culinaris-agglutinin-reactive fraction of AFP |
AGA | American Gastroenterology Association |
AIM | apoptosis inhibitor of macrophage |
AST | aspartate aminotransferase |
ALD | alcoholic liver disease |
ALT | alanine aminotransferase |
APRI | AST to platelet ratio index |
ARFI | acoustic radiation force impulse |
AUROC | area under receiver operating characteristics curve |
BMI | body mass index |
HA | hyaluronic acid |
PIIINP | aminoterminal propeptide of type III procollagen |
TIMP-1 | tissue inhibitor of matrix metalloproteinase type 1 |
CAC | coronary artery calcium |
CAD | coronary artery disease |
CAP | controlled attenuation parameter |
CHF | congestive heart failure |
CKD | chronic kidney disease |
COI | cutoff index |
CVD | cardiovascular disease |
CI | confidence interval |
CT | computed tomography |
DILI | drug induced liver injury |
eGFR | estimated glomerular filtration rate |
ELF | enhanced liver fibrosis |
ELISA | enzyme linked immunosolvent assay |
FAST | FibroScan–AST |
FIB-4 | Fibrosis-4 |
GGT | gamma glutamyltransferas |
HBV | hepatitis B virus |
HCV | hepatitis C virus |
HCC | hepatocellular carcinoma |
HF | heart failure |
HIV | human immunodeficiency virus |
HR | hazard ratio |
LSM | liver stiffness measurement |
MAFLD | metabolism dysfunction associated fatty liver disease |
M2BPGi | Mac-2 binding protein glycosylation isomer |
MRE | magnetic resonance elastography |
MRI | magnetic resonance imaging |
NAFL | nonalcoholic fatty liver |
NAFLD | nonalcoholic fatty liver disease |
NASH | nonalcoholic steatohepatitis |
NFS | NAFLD fibrosis score |
NIT | non-invasive test |
NPV | negative predictive value |
OCA | obeticholic acid |
OR | odds ratio |
PDFF | proton density fat fraction |
PIIINP | aminoterminal propeptide of type III procollagen |
PNPLA3 | patatin-like phospholipase domain-containing protein 3 |
PPV | positive predictive value |
SLKT | simultaneous liver kidney transplantation |
TIMP-1 | tissue inhibitor of matrix metalloproteinase type 1, |
T2D | type 2 diabetes |
UCAP | ultrasound-guided attenuation parameter |
US | ultrasonography |
VCTE | vibration-controlled transient elastography |
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Cutoff Values | No. of Studies (No. of Patients) | Summary Sensitivity, %, Mean (Range) | Summary Specificity, %, Mean (Range) | Summary PPV, %, Mean (Range) | Summary NPV, %, Mean (Range) |
---|---|---|---|---|---|
APRI | |||||
0.452–0.50 | 5 (729) | 72.9 (50.0–87.4) | 67.7 (43.1–91.0) | 44.8 (22.9–71.0) | 89.4 (84.9–95.0) |
0.54–0.98 | 7 (1,351) | 68.6 (61.0–76.2) | 72.7 (59.4–86.0) | 61.4 (46.9–76.2) | 77.6 (59.4–94.0) |
1.00 | 4 (1101) | 43.2 (27.0–67.0) | 86.1 (81.0–89.0) | 33.5 (26.0–40.0) | 89.8 (84.0–95.0) |
1.50 | 4 (682) | 32.9 (6.3–70.0) | 90.5 (74.5–97.0) | 55.5 (40.0–72.1) | 79.1 (73.2–87.2) |
FIB-4 index | |||||
1.24–1.45 | 10 (2759) | 77.8 (63.0–90.0) | 71.2 (55.5–88.0) | 40.3 (24.0–50.6) | 92.7 (88.0–98.0) |
1.51–2.24 | 8 (1533) | 77.0 (70.6–89.5) | 79.2 (67.1–93.6) | 66.4 (37.4–85.7) | 83.9 (58.6–97.2) |
2.67 | 6 (1910) | 31.9 (12.0–63.2) | 95.7 (88.3–98.7) | 66.0 (51.1–80.0) | 85.0 (79.4–92.6) |
3.25 | 6 (1890) | 37.3 (5.0–56.0) | 95.8 (89.0–100) | 72.5 (37.0–100) | 87.3 (78.5–94.0) |
5.31–10.62 | 4 (543) | 67.5 (50.0–100) | 80.8 (54.0–100) | 90.0 (80.0–100) | 85.1 (80.0–90.2) |
BARD | |||||
1.5 | 1 (242) | 83.0 | 59.0 | 34.0 | 93.0 |
2 | 14 (3057) | 75.2 (41.7–100) | 61.6 (32.5–88.9) | 38.3 (15.0–79.8) | 88.7 (49.6–100) |
3–4 | 5 (736) | 59.4 (33.3–85.2) | 75.1 (59.9–91.8) | 55.2 (24.0–69.2) | 81.0 (71.4–90.1) |
NFS | |||||
(−26.93)–(−2.16) | 2 (106) | 80.5 (78.0–83.0) | 69.5 (69.0–70.0) | None | None |
−1.455 | 10 (3057) | 72.9 (22.7–96.0) | 73.8 (42.9–100) | 50.4 (24.0–100) | 91.8 (81.3–98.1) |
(−1.31)–(0.156) | 5 (963) | 78.2 (69.0–86.4) | 71.7 (60.0–83.0) | 58.4 (34.0–80.8) | 82.1 (54.1–95.0) |
0.67–0.676 | 14 (3896) | 43.1 (8.3–100) | 88.4 (25.0–100) | 66.9 (26.0–100) | 88.5 (78.6–100) |
0.735 | 1 (235) | 68.4 | 88.3 | 53.0 | 93.5 |
Subjects | N | Nation | Dx | Observation Period | Over-all Mortality /Morbidity | Liver-Related Mortality/Morbidity | Liver Event | HCC | CVD Mortality | Extrahepatic Cancer |
---|---|---|---|---|---|---|---|---|---|---|
NAFLD [62] | 646 | Sweden | Biopsy | 19.9 ±8.7 years | FIB-4 ○ | FIB-4 ○ | ||||
NFS ○ | NFS ○ | |||||||||
Viral hepatitis-negative adults [61] | 14,841 | USA | General population | Median 19.3 years (IRQ, 17.5–21.1) years | APRI ○ | APRI ○ | FIB-4 ○ | APRI ○ | ||
FIB-4 ○ | FIB-4 ○ | |||||||||
NFS ○ | NFS ○ | |||||||||
Forns score ○ | Forns score○ | |||||||||
NAFLD [57] | 153 | Israel | Biopsy | 100 months (mean) | FIB-4 ○ | FIB-4 ○ | FIB-4 ○ | |||
NFS ○ | NFS ○ | NFS ○ | ||||||||
APRI × | APRI ○ | APRI ○ | ||||||||
NAFLD [68] | 180 | China | US | 6.6 (range 0.5–14.8) years | NFS ◎ | |||||
FIB-4 ○ | ||||||||||
APRI× | ||||||||||
BARD× | ||||||||||
NAFLD [58] | 646 | Japan | Biopsy | FIB-4 ○ | FIB-4 ○ | FIB-4 × | ||||
NAFLD [64] | 4073 | Japan | US | NFS ○ | NFS ○ | |||||
NAFLD with diabetes [63] | 284 | Australia | US | 51.4 (range 6.1–146). months | NFS × | |||||
FIB-4 × | ||||||||||
APRI × | ||||||||||
NAFLD [60] | 11,154 | US | US | 14.5 years | FIB-4 ○ | FIB-4 ○ | ||||
NFS ○ | NFS ○ | |||||||||
APRI ○ | APRI ○ | |||||||||
NASH [69] | 148 | Canada | biopsy | Median: 5 years (IQR: 3–8) | FIB-4 ○ | |||||
NFS ○ | ||||||||||
APRI ○ | ||||||||||
NAFLD [59] | 153 | US | biopsy | Median 104.8 (range, 3–317) months | NFS ◎ | |||||
FIB-4 ○ | ||||||||||
APRI ○ |
Over-Referral | Under-Referral | |
---|---|---|
FIB-4 index low COI | 1.3 | 1.45 |
GP | Work ↓ | Work ↑ |
Hepatologists | Work ↑ | Work ↓ |
Unnecessary liver biopsy | May increase | May reduce |
HCC early detection | Possible? | May delay diagnosis? |
Heath economic costs | High? | Low? |
Author | Subjects | Outcomes | Parameter Correlated with Pathological Improvement |
---|---|---|---|
Hamaguchi [121] | MAFLD (n = 39) | Hepatic fibrosis | ⊿HbA1c reduction |
Seko [122] | Steatohepatitis (n = 52) | NAS Hepatic fibrosis | ⊿ALT reduction ≥ 30% from baseline |
Hoofnagle [123] | Steatohepatitis (n = 139) without DM PIVENS trial | NAS Hepatic fibrosis | ⊿ALT reduction ≥ 30% from baseline or post-treatment ALT ≤ 40 IU/L |
Vilar-Gomez [124] | Steatohepatitis (n = 261) | NASH resolution w/o worsening fibrosis | ⊿BW reduction, absence of T2D ALT normalization, younger age, NAS < 5 |
Vuppalanchi | Adult steatohepatitis (n = 231) Pediatric MAFLD (n = 152) | Histological improvement | ⊿CK18 reduction (inferior to ⊿ALT reduction) |
Siddiqui [119] | MAFLD (n = 292) | Hepatic fibrosis | ⊿FIB-4 index, ⊿NFS, ⊿APRI |
Jayakumar [111] | Steatohepatitis, stage 2–3 (n = 54) Selonsertib (Phase 2) | Hepatic fibrosis | ⊿MRE |
Hepatic steatosis | MRI-PDFF > 25% reduction | ||
Chalasani [120] | Steatohepatitis (n = 200) FLINT trial (Phase 2) Placebo vs. OCA 72wk | Hepatic fibrosis | ⊿FIB-4 index ⊿APRI (⊿NFS: no correlation) |
Loomba | NAS ≥ 2 points reduction without worsening fibrosis | OCA(+), pretreatment NAS > 5, TG ≤ 154 mg/dL, INR < 1, AST < 49 IU/L, ⊿ALT at 24wk (>17 IU/L) |
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Sumida, Y.; Yoneda, M.; Tokushige, K.; Kawanaka, M.; Fujii, H.; Yoneda, M.; Imajo, K.; Takahashi, H.; Eguchi, Y.; Ono, M.; et al. FIB-4 First in the Diagnostic Algorithm of Metabolic-Dysfunction-Associated Fatty Liver Disease in the Era of the Global Metabodemic. Life 2021, 11, 143. https://doi.org/10.3390/life11020143
Sumida Y, Yoneda M, Tokushige K, Kawanaka M, Fujii H, Yoneda M, Imajo K, Takahashi H, Eguchi Y, Ono M, et al. FIB-4 First in the Diagnostic Algorithm of Metabolic-Dysfunction-Associated Fatty Liver Disease in the Era of the Global Metabodemic. Life. 2021; 11(2):143. https://doi.org/10.3390/life11020143
Chicago/Turabian StyleSumida, Yoshio, Masashi Yoneda, Katsutoshi Tokushige, Miwa Kawanaka, Hideki Fujii, Masato Yoneda, Kento Imajo, Hirokazu Takahashi, Yuichiro Eguchi, Masafumi Ono, and et al. 2021. "FIB-4 First in the Diagnostic Algorithm of Metabolic-Dysfunction-Associated Fatty Liver Disease in the Era of the Global Metabodemic" Life 11, no. 2: 143. https://doi.org/10.3390/life11020143