Noninvasive Markers of Fibrosis in the Assessment of Cirrhosis

Highly sensitive and specific to identify different stages of fibrosis

Applicable to the monitoring of disease progression or regression as part of the natural history of liver disease or treatment process

Readily available and inexpensive

Reproducible

Not susceptible to false positive results

In the following section, we review the markers that have been validated in METAVIR F4 fibrosis/cirrhosis stage for patients with HCV/HBV/NAFLD and ALD (Table 5.2).

Table 5.2

Specific and nonspecific liver fibrosis markers in cirrhosis

Test	Variables	Median AUROC	Median sensitivity (%)	Median specificity (%)
APRI	AST and platelet count	HCV0.83	HCV 76	HCV 72
		HBV 0.75	HBV 45^a	HBV 88^a
		EtOH 0.65	EtOH 44	EtOH 94
		NASH (??)	NASH 77	NASH 71
FIB-4	Age, AST, ALT, and platelet count	HCV 0.87	HCV 90	HCV 92
		HBV 0.89	HBV	HBV
		EtOH 0.80	EtOH —	EtOH —
		NASH 0.802	NASH 73	NASH 89
FibroTest	A2M, Haptogloben, GGT, TBil, apoprotein A1	HCV 0.87	HCV 74	HCV 82
		HBV 0.87	HBV 72	HBV 87
		EtOH 0.94	–	–
		NASH 0.860	NASH 73	NASH 92
ELF Score	Age, TIMP-1, PIIINP, and hyaluronic acid	HCV 0.94	HCV 93	HCV 86
		HBV	HBV	HBV
		EtOH	EtOH	EtOH
		NASH 0.89	NASH 91	NASH 69
FibroMeter	Hyaluronic acid, Platelet, PT, AST, A2M, urea, Age	HCV 0.92	HCV 72	HCV 90
		HBV 0.87	HBV 79	HBV 83
		EtOH 0.96^a
		NASH 0.94
HepaScore	Age, sex, TBil, A2M, hyaluronic acid, GGT	HCV 0.88	HCV 71	HCV 84
		HBV 0.91	HBV 87	HBV 86
		EtOH 0.91	EtOH 87	EtOH 89
		NASH 0.92	NASH 87	NASH 89

AUROC area under the receiver operating curve, APRI AST-to-platelet ratio index, AST aspartate aminotransferase, ALT alanine aminotransferase, EtOH ethanol, HBV hepatitis B virus, HCV hepatitis C virus, NASH nonalcoholic steatohepatitis, TBil total bilirubin, apoprotein A1 apolipoprotein-A1, A2M α-2-macroglobulin, GGT γ-glutamyl transpeptidase, ELF enhanced liver fibrosis, TIMP-1 tissue inhibitor of matrix metalloproteinase-1, PIIPNP amino-terminal peptide of type III procollagen, PT prothrombin time

^aData available for cohort containing patients with hepatitis B or C

Indirect (Class II) Markers of Liver Fibrosis

AST-to-Platelet Ratio Index

The AST-to-platelet ratio index (APRI) score is the simplest nonspecific liver fibrosis marker for predicting fibrosis [7]. The APRI incorporates only AST and platelet count and can be calculated using the formula:

$\text{APRI}=\text{AST}/\text{upper limit of normal AST}/\text{platelet count}\left( {{10}^{9}}/\text{L} \right)\times 100.$

The APRI is based on the premise that progression to cirrhosis and increasing portal pressure are associated with reduced production of thrombopoietin by hepatocytes, increased platelet sequestration within the spleen, and reduced clearance of AST [8].

HCV

The AUROC for APRI in cirrhosis was 0.83 with an optimal cutoff of 1.0, for a sensitivity and specificity of 76 and 72 %, respectively. A threshold of 2.0 exhibited a specificity of 91 % for diagnosing cirrhosis, but the sensitivity for this level was only 46 %. A major advantage of APRI is that it has been validated in special populations such as HIV/HCV coinfection [8].

HBV

APRI is one of the most widely used and validated biomarkers in HBV. It is able to predict cirrhosis with more accuracy than advanced fibrosis. A meta-analysis of APRI in 1798 HBV patients found a mean AUROC value of 0.75 in diagnosing HBV cirrhosis [16]. Degos et al. reported an AUROC of 0.77 (95 % CI, 0.73–0.81) with a sensitivity of 45 % (95 % CI, 39–52) and specificity of 88 % (95 % CI, 87–90.0) for APRI’s performance in predicting cirrhosis in a cohort of patients with either hepatitis B or C [19]. A positive predictive value (PPV) of 39 % (95 % CI, 33–45) and negative predictive value (NPV) of 91 % (95 % CI, 89–92) were observed [19].

Alcohol

In assessing cirrhosis secondary to ALD, a cutoff of 1.10 yielded an AUROC 0.648 (95 % CI, 0.43–0.87) with a sensitivity and specificity of 44 and 94 %, respectively. A PPV of 0.44 and NPV of 0.94 were reported [20].

NASH

Adams et al. used a cutoff of 0.54 for assessing NASH cirrhosis with a sensitivity of 77 %, specificity of 71 %, PPV 22 %, and NPV of 97 %. Specific noninvasive serum models developed for the prediction of cirrhosis in HCV are more useful for the prediction of advanced fibrosis or cirrhosis in subjects with NAFLD when compared to APRI [21].

Limitations to the interpretation of APRI include the presence of acute hepatitis; AST elevation from nonliver origin, thrombocytopenia from other causes such as bone marrow suppression related to alcohol or HCV-induced thrombocytopenia.

FIB-4

FIB-4 is an inexpensive method for the evaluation of liver fibrosis based on simple variables such as age, AST, ALT, and platelet count that are routinely measured. The index is not influenced by a patient’s body mass index [22]. It is calculated using the following formula:

$\text{FIB-}4=\frac{\text{age}\times \text{AST}\left( \text{U}/\text{L} \right)}{{{\left[ \text{PLT }\left( {{10}^{9}}/\text{L} \right)\times \text{ALT}\left( \text{U}/\text{L} \right) \right]}^{1/2}}}.$

Although FIB4 is a useful and simple scoring system, which is more accurate than the APRI for the diagnosis of cirrhosis, the values and cutoffs differ for the various etiologies of cirrhosis.

HCV

The FIB-4 index enabled the correct identification of patients with cirrhosis (F4) with an AUROC of 0.91 (95 % CI, 0.86–0.93). The FIB-4 index < 1.45 had an NPV of 95 % in excluding severe fibrosis, with a sensitivity of 74 % [21].For values outside 1.45–3.25, the FIB-4 index is a simple, accurate, and inexpensive method for assessing liver fibrosis and proved to be concordant with FibroTest results. The test was validated in HCV-induced cirrhosis with an observed AUROC of 0.87, sensitivity of 90 %, and specificity of 92 % [23].

HBV

FIB-4 can predict the presence of cirrhosis due to chronic HBV with a high degree of accuracy. A FIB-4 score ≤ 1.58 identified mild to moderate fibrosis (F0–F2), while a score > 5.17 predicted cirrhosis in CHB. The AUROC for HBV-induced cirrhosis was 0.89 [24].

NAFLD/NASH

When assessing the performance of FIB4 in NAFLD, the data were only provided for advanced F3/F4 fibrosis and not exclusively for cirrhosis. The AUROC was 0.802 (95 % CI, 0.76–0.85). The predicative values of the FIB4 index for advanced fibrosis (F3–F4) identified the presence of advanced fibrosis with 89 % accuracy, using a cutoff value of > 2.67 [25].

Alcohol

When applied to ALD-induced cirrhosis, FIB-4 yielded an AUROC of 0.80 (95 % CI, 0.72–0.86) [26].

FibroTest/FibroSure

FibroTest/FibroSure is a frequently used biomarker of liver fibrosis which was initially validated in patients with chronic HCV. It employs a patented calculation of a combination of five serum biochemical parameters [27]. These include α-2-macroglobulin, apolipoprotein A1, haptoglobin, l-glutamyltranspeptidase, and bilirubin. Advantages of FibroTest include widespread availability, high applicability (> 95 %), and inter-laboratory reproducibility [28]. It was developed using a linear scale from 0 to 1; cirrhosis is diagnosed when the FibroTest score is greater than 0.75. The higher the Fibrotest score, the more likely the diagnosis of cirrhosis is correct. A major cause of a false positive is the presence of hemolysis or Gilbert’s disease.

HCV

There have been multiple studies in HCV along with significant validation in normal population studies. The assessment of cirrhosis in HCV with FibroTest has an AUROC of 0.87 ± 0.04 (95 % CI, 0.80–0.94). Using a cutoff of 0.63, there was an observed sensitivity of 0.74, specificity of 0.82 with NPV, and PPV of 0.96 and 0.53, respectively [29].

HBV

Multiple large studies have been conducted assessing the performance of FibroTest in HBV-induced cirrhosis. The results yielded an AUROC of 0.87 (95 % CI, 62–79), with a sensitivity of 72 % (95 % CI, 62–79) and specificity of 87 % (95 % CI, 84–90 %). FibroTest had an NPV of 92 %, which established that it is an excellent test to rule out cirrhosis in this patient population [9]. Drawbacks to FibroTest include its cost, lack of external validation, and lack of specificity for liver disease as its results can be severely impaired by comorbidities, i.e., Gilbert’s syndrome or hemolysis [9].

Alcohol

Applying FibroTest to assess cirrhosis in the setting of alcohol yielded an AUROC of 0.94 ± 0.02 (95 % CI, 0.87–0.97) [26].

NASH

When FibroTest was applied to patients with NASH/NAFLD, a cut-off value of 0.57 resulted in an AUROC of 0.86 (95 % CI, 0.77–0.95) with a sensitivity of 73 %, a specificity of 92 %, PPV of 49 %, and NPV of 97 % for the diagnosis of cirrhosis [21].

Direct (Class I) Markers of Liver Fibrosis

Multiple etiologies of liver disease including HCV, HBV, NAFLD/NASH, and ALD can lead to liver fibrosis though integrated signaling networks that regulate the deposition of extracellular matrix [8, 30].This sequence of events drives the activation of hepatic stellate cells into a myofibroblast-like phenotype that is contractile, proliferative, and fibrogenic. Collagen and other extracellular matrix (ECM) components are deposited as the liver generates a wound-healing response to encapsulate injury. The direct (or class I) markers of liver fibrosis are usually fragments of the liver matrix components produced by hepatic stellate cells during the process of ECM remodeling, usually reflecting the deposition or removal of ECM.

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