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Marasco et al. Hepatoma Res 2020;6:32 I http://dx.doi.org/10.20517/2394-5079.2019.54 Page 3 of 17

invasive predictor of the progression of fibrosis in patients with chronic viral hepatitis. Over the years, several
studies have validated its role as a marker of hepatic fibrosis [18,19] .

[20]
An important study indicated that the Fib-4 index not only demonstrated the best predictive ability for
cirrhosis, but it was also an independent prognostic factor for postoperative hepatic insufficiency, overall
survival, and disease-free survival for HCC patients with radical liver resection. They also stratified patients,
with the cut-off value of 3.15, into Low and High fibrosis-4 groups. The High fibrosis-4 group had a higher
mean age (56.3 ± 10.4 vs. 47.7 ± 11.7, P < 0.01), higher MELD score (P = 0.001), and more patients with
Child-Pugh grade B (7.4% vs. 4.0%, P = 0.037).

[21]
These results have also been confirmed by other studies . Other groups have tried to use the ratio of
the remaining liver volume (FLRVR) and FIB-4 to predict PHLF and showed that FLRVR/FIB-4 was an
[22]
independent predictive factor of outcomes after liver resection in cirrhotic patients . The most recent
[23]
study by Zhou et al. demonstrated that the FIB-4 index was a more accurate predictive factor for PHLF
and survival than the Child-Pugh score; the authors thus proposed the use of the FIB-4 index to perform
pre-hepatectomy assessment citing a low incidence of PHLF in patients with FIB-4 ≤ 4.16. On the other
[24]
hand, Zhang et al. showed that FIB-4 was an independent predictor of PHLF only in minor hepatectomy
patients. Multivariate analysis in this subgroup of patients revealed that age (the older the patient, the more
the risk), Child-Pugh score and Albumin-Bilirubin score/spleen thickness ratio (ALBI/ST) were predictors
of PHLF in the APRI model, while Child-Pugh score, FIB-4, and ALBI/ST were found to be significant risk
factors of PHLF in the FIB-4 model. Thus, it is possible to conclude that FIB-4 is able to predict PHLF since
it is related not only to the degree of liver fibrosis but also, to the general performance of the patient since it
includes age.

Lok Index and Forns Index
The Lok Index and Forns Index are two other non-invasive markers of fibrosis. The Lok index is a non-
[25]
invasive tool introduced by an American research group as a predictor of cirrhosis development in patients
with chronic HCV-hepatitis. It is based on simple laboratory parameters and calculated through the following
3
3
formula: log odds (predicting cirrhosis) 5.56 - 0.0089 × platelet count (× 10 /mm ) + 1.26 × AST/ALT ratio +
5.27 × INR. Some studies have correlated the value of the Lok index with the grade of fibrosis. For example,
[26]
Ma et al. showed that FIB-4 and Lok’s model were the most effective models for distinguishing significant
[27]
and extensive fibrosis. Zhou et al. found that a Lok index cut-off value of 0.4531 could further spare 24.2%
[28]
[27]
of gastroscopies without missing high-risk varices (HRVs) . Since this is a fibrosis marker, Mobarak et al.
found that it was also able to predict HCC development. To date, the Lok-index is predominantly used for
the prediction of fibrosis and cirrhosis but not PHLF.
[29]
The Forns Index was developed by Forns et al. in 2002, before the introduction of transient elastography
techniques. It was first proposed as a non-invasive tool for the detection of patients with non-significant liver
fibrosis. It is calculated using four variables (age, gamma glutamyl transferase, total cholesterol and platelet
count) with the following formula: 7.811 - 3.131 × ln [platelet count (10 /L)] + 0.781 × ln [gamma GT (IU/L)]
9
+ 3.467 × ln [age (years)] - 0.014 × [cholesterol (mg/dL). The first studies on the Forns Index (FI) highlighted
its accuracy in identifying patients with different stages of fibrosis and cirrhosis [29,30] . A recent study showed
that the Forns index is also useful in evaluating liver functionality and the degree of liver fibrosis, so it is able
[31]
to predict HCC recurrence and patient survival . However, to date, little is known on the use of the Forns
index to predict PHLF.

ALBI score
Another biochemical index used in clinical practice is the Albumin-Bilirubin (ALBI) score, which was
[32]
introduced by Johnson et al. to evaluate liver function in patients with hepatocellular carcinoma. It was