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
APA StyleSumida, Y., Yoneda, M., Tokushige, K., Kawanaka, M., Fujii, H., Yoneda, M., Imajo, K., Takahashi, H., Eguchi, Y., Ono, M., Nozaki, Y., Hyogo, H., Koseki, M., Yoshida, Y., Kawaguchi, T., Kamada, Y., Okanoue, T., Nakajima, A., & Japan Study Group of NAFLD (JSG-NAFLD). (2021). FIB-4 First in the Diagnostic Algorithm of Metabolic-Dysfunction-Associated Fatty Liver Disease in the Era of the Global Metabodemic. Life, 11(2), 143. https://doi.org/10.3390/life11020143