Cirrhosis of Wilson’s disease: High and low cutoff using acoustic radiation force impulse (ARFI) -Comparison and combination with serum fibrosis index

Abstract

BACKGROUND:

Acoustic Radiation Force Impulse (ARFI), Fibrosis-4(FIB-4) and Aspartate transaminase to platelet ratio index (APRI) are valuable non-invasive methods to evaluate fibrosis in hepatitis virus. Yet, they are rarely used in Wilson’s disease.

OBJECTIVE:

Evaluate the diagnostic efficacy of ARFI, FIB-4, APRI, combined detection in cirrhosis with WD, and speculate the optimal high, low cutoff.

METHODS:

This retrospective study was authorized by hospital ethics Committee (number:2021MCZQ02). 102 patients with WD completed ARFI and laboratory examination on the same day. The intraclass correlation coeffcient (ICC) of ARFI among three sonographers was 0.896 (95%CI:0.859–0.925, p = 0.000). The stage of liver involvement was classified into 5 categories according to clinical manifestations, laboratory examination, and liver morphologic characteristics: I, normal; II, biochemical abnormal only; III, abnormal liver morphologic features without sighs of cirrhosis; IV, clinical and imaging sighs of compensateded cirrhosis (Child-Pugh A); V, decompensated cirrhosis (Child-Pugh B and C). This stage system served as the reference standard. The diagnostic efficacy was analyzed by Logistic regression, ROC curve. The optimal low cut-off with high sensitivity (SE) and low negative likelihood ratio (NLR) and high cut-off with high specificity (SP) and positive likelihood ratio (PLR) were derived.

RESULTS:

The diagnostic value of ARFI (0.85, 95%CI:0.77–0.92, p = 0.000) in distiguishing cirrhosis with WD was higher than FIB-4 (0.59, 95%CI: 0.47–0.70, p = 0.127), APRI (0.70, 95%CI: 0.59–0.81, p = 0.000). The low, high cut-off of ARFI for excluding, diagnosing cirrhosis with WD was 1.47 m/s(SE: 98%, NLR:0.09), 2.11 m/s(SP:98%, PLR:27.4), 37 (36%) patients could be spared a liver biopsy. When ARFI was 1.47∼2.11 m/s, liver biopsy was recommended. After combined with ARFI, the AUROC of FIB-4, APRI were increased respectively (p < 0.001), there were not different between ARFI and combined detection(p > 0.05).

CONCLUSION:

ARFI could replace some unnecessary liver biopsy according to high diagnostic efficacy for identifying cirrhosis of WD. The combined detection can also be used as an important model to predict cirrhosis in WD.

Keywords

Wilson’s disease ARFI APRI FIB-4

1 Introduction

Wilson’s disease (WD) is an autosomal recessive disease with very low morbidity. It usually occurs in children and adolescents, and often involves the liver leading to cirrhosis [1 –3]. If WD is not diagnosed in time and given proper treatment, it will eventually develop into a series of serious complications such as decompensated cirrhosis with portal hypertension.

Traditional evaluation and follow-up of liver fibrosis was achieved through liver biopsy. However, in recent years, it has become less and less clinically used because of its imperfect [4, 5]. Non-invasive assessment [6] is better tolerated, safer, and easier to accept by patients, and can be repeated as often as necessary. In addition, most of them are much cheaper than liver biopsy. These non-invasive tests include US elastography, MRI elastography and Serum fibrosis model, etc.

Conventional MRI is good at detecting morphological changes of liver, while MR elastography is more sensitive in assessing liver fibrosis and cirrhosis, and because it is operator independent and not easily affected by patient’s body type. It has proven to be effective for distinguishing lower and higher stages of cirrhosis, but, due to its economic cost and time-consuming, and its accuracy in measuring liver stiffness affected by some factors, wider clinical application is limited [7]. In the past 20 years, US elastography have developed rapidly, ARFI is one of the most useful imaging elastography methods. It has been proven to be a reliable method to predict the severity of fibrosis in HCV patients, and the measurement failure rate is low [8, 9].

APRI and FIB-4 have been verified to be useful index which can identify cirrhosis with acceptable accuracy evaluated in HCV or HBV [10 –12]. WHO guidelines suggested: in the absence of conditions for elastography or fibrotest, APRI or FIB-4 should be used to assess the degree of liver fibrosis in hepatitis C [13].

However, these techniques are mostly used in cirrhosis caused by viral, there are few studies on these indicators used in WD, and lack of diagnostic criteria, so the purpose of this study was to evaluate the feasibility and effectiveness of cirrhosis caused by WD through these indicators.

2 Materials and methods

2.1 Patients

From November 3, 2018, to November 30, 2020, 102 patients (mean age, 28; age range, 7–55 years) were diagnosed as WD in our hospital. All relevant medical data was extracted from the electronic medical record system and retrospectively analyzed. The study was carried out under the ethical guidelines of the “Helsinki Declaration” and approved by the Ethics Review Committee of the first affiliated Hospital of Anhui University of Traditional Chinese Medicine (registration number:2021MCZQ02). Inclusion criteria: patients with WD were included in the study: (1) Clinical diagnosis can be confirmed by meeting the following 4 items: 1) Liver symptoms (except viral, drug, autoimmune liver diseases, etc.) or extrapyramidal symptoms, 2) K-F (+), 3) ceruloplasmin is below the lower limit (0.2 g/L), 4) 24-hour urine copper >100 ug/d, children > 40 ug/d, (2) genetic diagnosis: those who do not meet the clinical diagnostic criteria, if two known pathogenic mutations of ATP7B gene testing are detected, WD can be genetically diagnosed [14, 15]. Exclusion criteria: (1) advanced age (> 65 years old); (2) complicated with other types of hepatitis, history of excessive alcohol intake; (3) rheumatism that may lead to fibrosis; (4) diabetes or renal failure.

2.2 Methods of measurement

On the same day, patients were investigated about demographic characteristics, smoking history, drinking history, medical history, and course of the disease. Eight hours after fasting, the patients underwent clinical examination, ultrasound examination recording liver morphological characteristics, portal venous velocity (PVV), diameter of portal vein (PVD), the size of spleen, ascites, ARFI, and laboratory examinations including alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum albumin (ALB), prothrombin time (PT), serum copper, ceruloplasmin, serum zinc, 24-hour urine copper, 24-hour urine zinc, platelet count (PLT), creatinine, etc.

APRI: (AST[U/L]/ULN)/PLT(109/L) x100, The AST upper limit of normal (ULN) is 40U/L. FIB-4: (Age(yrs)×AST[U/L])/(PLT(109/L) x(√ALT[U/L]) [16].

ARFI and conventional Ultrasound medical examination were performed by three sonographers (with at least 10 years of experience in abdominal ultrasound diagnosis) in a double-blind situation using an US system (SIEMENS ultrasound system S2000) with a convex-array probe 4C1 (1∼4 MHz), and a linear-array probe 9L4 (4∼9 MHz), equipped with ARFI imaging system, and then the three doctors had no objection to the results and finally a consensus was reached. First of all, the routine B-ultrasound examination was conducted, and the convex array low-frequency probe was used to scan the whole liver (Fig. 1A), and the linear array probe high-frequency linear array probe was used to detect the detailed feature of the hepatic capsule (Fig. 1B, C) and parenchyma (Fig. 1D). ARFI: patients took the left recumbent position, lifted the right upper arm to open the intercostal space as far as possible to facilitate ultrasonic detection, the patient was in a steady breathing state, ARFI technology locates the target area (5 mm×10 mm) using the B-mode ultrasonic mode to avoid non-target structures such as ductal structures, sampling frame selected S5 or S8 segment, the depth was 4–6 cm, the distance from the capsule was at least 2–3 cm, and must be perpendicular to the liver capsule (Fig. 1E). The data must be measured 10 times in the same area, and at least 6 times were required to be valid, and the mean value was obtained in accordance with IQR/Median (quartile/median) ≤0.3 [17].

Fig. 1

A: The low-frequency convex array probe showed that the echo of the liver parenchyma was thickened and multiple hypoechoic nodules were seen. Figure1B: High frequency linear array probe showed smooth liver capsule. Figure1C: The liver capsule was not smooth; Figure1D: Honeycomb hypoechoic nodules were seen in the parenchyma of the liver. Figure1E: liver stiffness measurement (LSM) using ARFI.

2.3 The staging system for liver involvement of WD

In previous studies of chronic hepatitis B, C or nonalcoholic steatohepatitis, the cut-off value was based on liver biopsy as a reference standard, but it is not very suitable for WD. Fibrosis with WD is due to copper deposition in liver cells, the distribution of copper in the liver is not uniform [4], so the degree of liver fibrosis is also inconsistent. The limited tissue obtained by liver biopsy cannot objectively represent the copper content and stage of fibrosis of the whole liver, so it cannot guide clinical treatment very effectively. Moreover, it is a traumatic examination, which cannot be accepted by patients, while non-invasive assessment is more easily accepted. Therefore, this study could not obtain large-scale pathological results as the reference, but according to the following criteria to classify the degree of liver involvement, previous study [17] had also referred to this staging system.

The staging system for liver involvement of WD [18, 19]: I, normal without laboratory or clinical signs of liver involvement; II, raised ALT and AST with normal liver morphologic features; III, abnormal liver morphologic features without sighs of cirrhosis; IV, clinical and US sighs of compensateded hepatic cirrhosis (Child-Pugh A), the diagnosis of compensateded cirrhosis was made by a comprehensive consideration of clinical manifestation, medical history, blood biochemistry, and imaging diagnosis. The ultimate diagnosis should meet the following two or more standards, which can be clinically diagnosed as compensateded cirrhosis. (1) Gastroscopy showed esophageal and gastric varices. (2) Ultrasound, CT, and MRI suggest features of liver cirrhosis or portal hypertension. (3) Hypersplenism was characterized by thrombocytopenia (<100×109/L) with no other explanation. (4) The decrease of liver synthetic function was characterized by prolonged prothrombin time (>13 sec) more than 7 days after discontinuation of thrombolytic drugs or anticoagulants, and decreased serum albumin (<35 g/l) excluding malnutrition or renal disease; V, decompensated heptic function (Child-Pugh B and C) or cirrhosis with severely impaired. Decompensated liver cirrhosis is often accompanied by ascites, gastrointestinal hemorrhage, hepatic encephalopathy, combined disease history, laboratory test results and evidence of typical portal hypertension and liver cirrhosis, it is easy to make a diagnosis.

2.4 Data analysis and statistical methods

Statistical analysis was carried out by using spss 23.0 software. The intraclass correlation coefficient (ICC) was analyzed to evaluate the consistency of ARFI measured by these sonographers, the IC over 0.75 represents high consistency. For quantitative variables, those with normal distribution were represented by $\bar{x} \pm s$ , those with non-normal distribution were represented by median (interquartile range: IQR). Kruskal-Wallis H test was used for comparison ARFI, APRI and FIB-4 between 5 groups. Receiver operating characteristic (ROC) was used to evaluate the diagnostic efficacy of ARFI, APRI and FIB-4, respectively. According to different diagnostic environments, the optimal high and low cut-off values were determined taking account of sensitivity (SE), negative likelihood ratio (NLR), specificity (SP) and positive likelihood ratio (PLR). The predictive probability of WD’s cirrhosis using combined diagnosis was calculated by Logistic regression analysis, and the diagnostic efficiency was analyzed by ROC curve. The difference was statistically significant (p < 0.05).

The optimal low cut-off value must have high SE and low NLR, when NLR < 0.1, it can be used as evidence to exclude the disease and avoid missed diagnosis, the possibility of true negative is very high when the measurement is lower than the low cut-off point; On the contrary, the optimal high cut-off value must have high SP and PLR, when PLR > 10, it can be used as evidence for the diagnosis of the disease, to avoid misdiagnosis and excessive medical treatment, the possibility of true positive is very high when the measurement is higher than the high cut-off point; When the measurement is between the high and low cut-off points, liver biopsy should be considered to further confirm [20 –22].

3 Results

3.1 Demographic characteristics of the study subjects

A total of 122 patients with WD were originally enrolled in this study. Among them, 5 patients did not complete the examination on the same day, 6 patients had incomplete data, and 9 patients had unclear elastography images caused by the involuntary tremor. Finally, 102 patients were included in the study. According to the classification criteria described above, the patients were divided into 5 groups, the characteristics of participants were shown in Table 1.

Table 1
Characteristics of participants

Demographics Total I II II IV V P

N 102 4 4 52 30 12

Age(y) (mean±SD) 28±10.0 29.3±6.0 12.2±3.0 27.6±1.3 29.9±1.9 33.7±3.2 0.023

Male/female 62/40 0/4 2/2 31/21 19/11 10/2

Serum biomarkers

AST (U/L, 15–40) 24 (12) 24 (10) 40 (76) 22 (11) 24 (10) 32 (11) 0.009

ALT (U/L, 9–50) 22 (21) 23 (15) 92 (146) 20 (107) 23 (22) 24 (15) 0.023

PLT (10⁹/L, 125–350) 147 (96) 231 (241) 242 (256) 159 (76) 120 (143) 38 (189) 0.002

PT (sec, 9–13) 11.4 (1.9) 11.1 (0.5) 11.3 (2.4) 11.1 (1.3) 11.6 (1.7) 16.4 (3.4) 0.000

ALB (g/L, 40–55) 39.8 (5.7) 38 (4) 44 (12) 41 (4) 39 (5) 30 (8) 0.000

ultrasonics

PVV (cm/s) 17.1±3.0 19.7±2.4 16.4±0.2 15.7±0.8 17.2±0.62 15.2±1.0 0.266

PVD (mm) 12 (3) 11.5 (3) 9 (3) 11 (3) 12 (4) 14 (3) 0.004

Demographics	Total	I	II	II	IV	V	P
N	102	4	4	52	30	12
Age(y) (mean±SD)	28±10.0	29.3±6.0	12.2±3.0	27.6±1.3	29.9±1.9	33.7±3.2	0.023
Male/female	62/40	0/4	2/2	31/21	19/11	10/2
Serum biomarkers
AST (U/L, 15–40)	24 (12)	24 (10)	40 (76)	22 (11)	24 (10)	32 (11)	0.009
ALT (U/L, 9–50)	22 (21)	23 (15)	92 (146)	20 (107)	23 (22)	24 (15)	0.023
PLT (10⁹/L, 125–350)	147 (96)	231 (241)	242 (256)	159 (76)	120 (143)	38 (189)	0.002
PT (sec, 9–13)	11.4 (1.9)	11.1 (0.5)	11.3 (2.4)	11.1 (1.3)	11.6 (1.7)	16.4 (3.4)	0.000
ALB (g/L, 40–55)	39.8 (5.7)	38 (4)	44 (12)	41 (4)	39 (5)	30 (8)	0.000
ultrasonics
PVV (cm/s)	17.1±3.0	19.7±2.4	16.4±0.2	15.7±0.8	17.2±0.62	15.2±1.0	0.266
PVD (mm)	12 (3)	11.5 (3)	9 (3)	11 (3)	12 (4)	14 (3)	0.004

Data were presented as median (IQR) for non-normally distributed variables, and $\bar{x} \pm s$ for normally distributed variables; AST = Aspertate Aminotransferase; ALT = glutamic-pyruvic transaminase; PLT = platelets; pT = prothrombin time; ALB = albumin; PVD = diameter of portal vein; PVV = portal venous velocity.

3.2 Characteristics of ARFI, APRI, FIB-4 at different stages of liver involvement with WD

Figure 2 shows the distributions of ARFI, APRI, FIB-4 at different degrees. The difference of ARFI (x² = 36.110, P = 0.000), APRI (x² = 23.662, P = 0.000) among the 5 stages was statistically significant, while there was not statistically significant difference in FIB-4 among the 5 stages (x² = 6.612, P = 0.158). The more severe the liver damage, the higher the ARFI value (Fig. 2A). The intraclass correlation coeffcient (ICC) of ARFI among the sonographers was 0.896 (95%CI:0.859–0.925, p = 0.000).

Fig. 2

Characteristics of ARFI, APRI, FIB-4 at different stages of liver involvement with WD. A: Comparison of the ARFI; B: Comparison of the APRI; C: Comparison of the FIB-4. The box distance in the figure represents the interquartile range(IQR), and the horizontal thick line represented the median (M). O = outside values, ^* = outliers.

3.3 Diagnosis efficiency and cut-off value

The AUROC of FIB-4, APRI and ARFI in the diagnosis of WD’s cirrhosis were 0.59 (95%CI, 0.47–0.70, p = 0.127), 0.70 (95%CI, 0.59–0.81, p = 0.000), 0.85 (95%CI, 0.77–0.92, p = 0.000), respectively (Fig. 3), and the cutoffs of these detections were shown in Table 2. The diagnostic efficiency of ARFI was better than APRI (z = 2.393, p = 0.017) and FIB-4 (z = 4.585, p = 0.000), the low cut-off of ARFI was 1.47 m/s (SE:98%, NLR:0.09), the diagnosis of WD’s cirrhosis could be ruled out in 15%of all patients when LSM was lower than the low cut-off, the high cut-off was 2.11 m/s (SP:98%, PLR:27.4), cirrhosis could be diagnosed in 21%of all patients when LSM was higher than the high cut-off, hence, about 37 (36%) patients would not need liver biopsy, when the LSM was located in 1.47∼2.11 m/s, it was recommended that the histological examination of liver biopsy should be further confirmed.

Fig. 3

A: ROC curves of FIB-4, ARFI and combined detection (ARFI + FIB-4) for identifying cirrhosis of WD; B: ROC curves of APRI, ARFI and combined detection (APRI + ARFI) for identifying cirrhosis of WD.

Table 2

The optimal cutoff of ARFI, APRI, FIB-4

	Se	Sp	PLR	NLR
ARFI (m/s)
Low cut-off 1.47	98%	/	/	0.09
High cut-off 2.11	/	98%	27.40	/
APRI
Low cut-off 0.20	93%	/	/	0.68
High cut-off 1.45	/	98%	10.90	/
FIB-4
Low cut-off 0.40	93%	/	/	0.51
High cut-off 1.98	/	98%	12.3	/

Se = Sensitivity. Sp = Specificity. PLR = Positive likelihood ratio. NLR = negative likelihood ratio.

After combined with ARFI, the AUROC of FIB-4, APRI were significantly increased, the AUROC of FIB-4 + ARFI in the diagnosis of cirrhosis with WD was 0.87(95%CI, 0.80–0.94, p = 0.000) (Fig. 3A), which was higher than that of FIB-4 alone(z = 4.637, p = 0.000). The AUROC of APRI + ARFI in the diagnosis of cirrhosis with WD was 0.90 (95%CI, 0.83–0.96, p = 0.000) (Fig. 3B), which was higher than that of APRI (z = 3.742, p = 0.000). However, there were not statistically different between the AUROC of ARFI and combined detection (ARFI versus FIB-4 + ARFI: z = –1.391, p = 0.164, ARFI versus APRI + ARFI: z = –1.738, p = 0.08, FIB-4 + ARFI versus APRI + ARFI: z = –1.159, p = 0.247).

4 Discussion

Liver cirrhosis refers to the result of a repair response to chronic liver injury caused by different factors, such as viruses, parasites, and metal trace elements. The extracellular matrix of fibrous scar tissue wraps the injured area, and the injury and repair are carried out repeatedly. With the increase of fibrous tissue, liver fibrosis is formed, and then finally lead to cirrhosis. The balance of copper metabolism is mainly maintained in the liver. Once the balance is broken, too much free copper will be deposited in the liver, leading to lobular cirrhosis, such as WD [23]. Therefore, early diagnosis of cirrhosis and timely treatment is very crucial to the management in the chronic liver disease. As far as we know, this article was the first article focus on the cut-off values of diagnosing and excluding cirrhosis with WD using ultrasound elastography. Besides, statistical analysis was not only based on sensitivity and specificity but also combined with PLR and NLR to increase the credibility.

At present, there were many laboratory indicators for evaluating liver fibrosis, including established serum markers (APRI, FIB-4, Fibrotest, Forns Index, HA, HepaScore, Fibrometer, etc.) and experimental serum markers [6]. APRI and FIB-4 had been extensively used in the evaluation of liver fibrosis with HBV and HCV. Previous researches had shown that serological indexes (FIB-4 and APRI) were recommended to evaluate cirrhosis of viral hepatitis because of their good diagnostic efficacy [24 –26]. However, it should be noted that in this study these indexes were not suitable for cirrhosis caused by WD. The diagnostic value of FIB-4 in this study was particularly inefficient, AUROC:0.59, APRI only had medium diagnostic value, AUROC:0.70, the results showed that the effect of APRI and FIB-4 in the diagnosis of WD’s cirrhosis did not reach the high diagnostic efficiency of cirrhosis caused by hepatitis viral, a meta-analysis exhibit the AUROC of FIB-4 identifying hepatitis B cirrhosis was 0.85 [24], another study about hepatitis C suggests the AUROC of APRI identifying cirrhosis was higher than 0.8 [25]. But, this study showed that only these single serum fibrosis indexes were of low value in predicting WD’s cirrhosis.

The traditional imaging techniques for evaluating liver cirrhosis include CT, MRI, and US, which can make qualitative judgments on the morphologic changes of liver and related organs. The innovative techniques such as US elastography, MR elastography, Fibro CT are used to quantitatively measure liver stiffness to reflect the degree of liver fibrosis [6]. In this study, liver stiffness was measured by ARFI imaging technology. ARFI was a US-based imaging technology. ARFI ultrasonic probe sends out short pulses, and then generates shear wave tracking, a specific acoustic pulse sequence is used to collect the shear wave signals in the tissue, and then calculate the transverse shear wave speed of the organization, which reflects the hardness of the organization, the higher the speed, the greater the hardness of the organization. Compared with strain elastography, ARFI did not need to exert pressure manually, overcomes the limitation that traditional elastography could not exert pressure on deep tissue, and avoids the interference of subjective factors of diagnostics. It had been proved to have high consistency among different operators [17 , 27].

This study showed that the value of ARFI (AUROC 0.85(95%CI:0.767,0.922) in the diagnosis of WD’s cirrhosis was obviously higher than that of FIB-4 and APRI. Although a relatively mature standard for the diagnosis of cirrhosis caused by other diseases has formed using elastography, there were few studies about WD’s cirrhosis using elastography [28, 29], and the diagnostic criteria had not yet been formed. The cut-off points of LSM were different with different etiology. A guideline suggested that the cutoff values for diagnosing or excluding cirrhosis with Hepatitis C were 14.6 kPa, 10 kPa [30]. A study involving viral hepatitis, alcoholic hepatitis, and autoimmune hepatitis cirrhosis suggested that the cut-off value of cirrhosis caused by these etiologies was 2.4 m/s [31]. This study inferred the high cut-off for diagnosing WD’s cirrhosis was 2.11 m/s (E = 13.3 kPa), E = 3ρCs2, E was the absolute value of elastic modulus; ρ was tissue density, assumed to be 1000 Kg/m3 [32, 33]; Cs was the propagation velocity of shear wave in human tissue. When LSM>2.11 m/s, WD’s cirrhosis could be diagnosed. The low cut-off point was 1.47 m/s (6.48 kPa), so when LSM<1.47 m/s, WD’s cirrhosis could be excluded. When the LSM was located in 1.47∼2.11 m/s, liver biopsy was recommended to further confirm. Compared with other causes of cirrhosis, this study showed that the cut-off of LSM for diagnosing WD’s cirrhosis was lower than others, and the possible reasons for this phenomenon are as follows: first, in patients with WD, the distribution of copper is plaque, and it is mainly deposited in hepatocytes around the portal vein or regenerated nodules [34]. According to routine ultrasound examination in this study, we found that in some cases, there were many nodular hypoechoic areas along the portal vein in the liver, which were honeycomb, while the measurement principle of ARFI was that it must avoid the portal vein, so the measurement location was often a little away from the portal vein, whether this measurement method would underestimate the LSM of patients with WD, it needs to be verified by further study. Second, the onset age of WD is in childhood or adolescence, the clinical manifestations appear early, and then there will be a stable course of treatment, which made the degree of cirrhosis less severe [17, 35]. Third, some studies have suggested that compared with hepatitis B, cirrhosis with WD show mild elevation of transaminase, symptoms of portal hypertension, higher ALB, and lower PT [36], but transaminase, ALB, and PT are related to liver inflammation and liver injury, and the state of liver inflammation affects liver stiffness as well as the degree of fibrosis [37], while elastography just evaluates the stiffness of the liver. The data of this study showed that the median of AST and ALT were in the normal range, and the proportion of patients whose AST or ALT higher than normal was relatively low, which only accounted for 20.6%, 11.7%respectively. Therefore, due to the possible low inflammatory state of the liver, the LSM of WD’s cirrhosis may be lower than that of other causes in the same degree of fibrosis.

The diagnostic efficiency of combined detection (FIB-4 + ARFI, APRI + ARFI) were significantly higher than FIB-4 or APRI alone. Very few small-sample studies had done relevant reports [38], the previous studies pointed out that the diagnostic efficacy of combined diagnosis was higher than that of single detection but did not give a detailed introduction on how the combined prediction model predicted the occurrence of cirrhosis. Using logistic regression to analysis the combined detection, the results was a predictive probability, at the same time, a regression equation was established, and the diagnostic efficiency was proved by ROC curve. Therefore, the combined detection could be used as a model to speculate the occurrence of WD’s cirrhosis when the mesurements of ARFI, FIB-4 or APRI were imported into the equation. Because the factors included in this study were limited, in the future, after including multiple factors, we will further study a better, simple and efficient predictive model of liver cirrhosis or significant fibrosis that is convenient for clinical practice.

There were some limitations in this research. First, this study was a retrospective study, and an RCT study may be more ideal; second, the sample size was not large enough; third, this study was only conducted in a single-center. Fourth, Liver biopsy is invasive, furthermore, because of the uneven distribution of liver copper and fibrosis, a small number of liver biopsy specimens would not reflect the whole pathologic change of the liver, therefore, this study unable to get enough pathology as a reference.

5 Conclusion

ARFI could replace some unnecessary biopsy procedures according to high diagnostic efficacy for identifying WD’s cirrhosis. The combined detection (FIB-4 + ARFI, APRI + ARFI) can also be used as an important model to predict the cirrhosis of WD.

Footnotes

Acknowledgments

Yan Li and Jianbing Ma collected clinical data, Yan Li drafted the manuscript, Yan Li is the First Author, and Jianbing Ma is the co-first author. Xiaoli Zhu and Jingping Wang designed the study and Xiaoli Zhu is the corresponding author, Jingping Wang is the co-corresponding author. All authors read and approved the final manuscript.

Conflict of interest

The authors have no conflict of interest to disclose.

Funding

Jiaxing Key Disciplines (No: 2019-fc-06).

The key talent project of science and education funded by Jiangsu Provincial Department of Health (No: ZDRCA2016038).

The General Project of National Natural Science Foundation of China (No: 81771945).

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the he first affiliated hospital of Anhui University of Traditional Chinese Medicine. The requirement for individual consent was waived by the committee because of the retrospective nature of the study.

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