Strain elastography for noninvasive assessment of liver fibrosis: A prospective study with histological comparison

Abstract

The aim of this study was to prospectively evaluate the diagnostic performance of strain elastography for the assessment of liver fibrosis in patients with chronic liver disease using Ishak (0–6) histology stage as a reference standard. Ninety-eight consecutive patients with suspected chronic liver disease scheduled for liver biopsy (n = 78) or histologically confirmed cirrhosis (n = 20) were enrolled. Liver fibrosis Index (LF Index) calculated by strain elastography, liver stiffness by transient elastography and serum fibrosis markers (aspartate aminotransferase-to-platelet ratio index and King’s Score) were measured. Spearman’s correlation coefficient between the LF Index, liver stiffness, serum fibrosis markers and fibrosis stage were calculated and compared using areas under the receiver-operating characteristics (AUROCs) curves. Among 73 patients who underwent strain elastography, there was weak correlation between fibrosis stage and the LF Index (Spearman’s: ρ = 0.385 for Ishak score; P = 0.001). Among 52 patients who underwent strain elastography and transient elastography, the AUROC values using LF Index, transient elastography, aspartate aminotransferase-to-platelet ratio index and King’s Score for diagnosing significant fibrosis (Ishak score ≥ 3) were 0.79, 0.87, 0.86 and 0.85, respectively (P < 0.0001) and for diagnosing severe fibrosis/cirrhosis (Ishak score ≥ 5) were 0.83, 0.94, 0.92 and 0.92, respectively (P < 0.0001). When comparing the diagnostic performance using LF Index, transient elastography, aspartate aminotransferase-to-platelet ratio index and King’s Score, transient elastography shows a significantly higher AUROC value than LF Index in detecting severe fibrosis (P = 0.0149). The diagnostic performance of LF Index calculated by strain elastography was not statistically significantly different to the other noninvasive tests for the assessment of significant liver fibrosis but inferior to transient elastography for the assessment of severe fibrosis/cirrhosis.

Keywords

Liver ultrasound real-time elastography liver fibrosis strain elastography

Introduction

Assessment of the degree of liver fibrosis is important in patients with chronic liver disease to estimate prognosis to determine surveillance intervals and guide treatment decisions. At present, liver biopsy is used as the reference standard for the assessment of liver fibrosis. However, it is an invasive method associated with patient discomfort and, on occasion, with serious complications.¹ In addition, the accuracy of liver biopsy is limited due to significant intra- and interobserver variability and sampling errors.^2–4

Noninvasive ultrasound-based methods for the assessment of liver fibrosis in patients with chronic liver disease have been widely adopted in recent years using a measure of liver “stiffness,” termed as elastography. A variety of elastography methods are available for the assessment of liver fibrosis. Transient elastography (TE) and shear wave elastography (SWE) methods, including point SWE (pSWE) and multidimensional SWE (two-dimensional (2D)-SWE and three-dimensional (3D)-SWE), all measure the propagation speed of a shear wave transmitted from a transducer through the liver.⁵ As hepatic fibrosis progresses, the propagation speed increases. The shear waves can be generated by an external push (TE), by ultrasound radiation force enabling a single measurement (pSWE) or by an image (2D-SWE and 3D-SWE).

In contrast to the above elastography methods, strain elastography (SE) diagnoses hepatic fibrosis using the tissue deformation (strain) within the liver induced by an external compression.^6,7 From transducer-induced deformation of tissues measured between consecutive echo signal frames, a colour-coded map of the strain distribution (elastogram) is overlaid on the B-mode image. The extent of the tissue deformability of the tissue (strain) is related to its stiffness. SE provides a qualitative measurement of higher or lower stiffness, which is displayed with color-coded mapping.⁶ Quantitative stiffness values can be obtained by converting the colour mapping scale to a numerical scale using various measurements generated by the elastography module.⁸ The first commercial application of SE was developed by Hitachi Medical Systems (Tokyo, Japan) and given the real-time modality of this technique, it is frequently called real-time tissue elastography (RTE). Several studies have demonstrated the usefulness of RTE in the assessment of liver fibrosis.^9–17 Despite promising results for the prediction of liver fibrosis in Asian patients, several studies have shown its performance in European patients to be inferior to TE.^11,18 In view of this, guidelines recommend that further research regarding the use of SE in the assessment of liver fibrosis is required.¹⁹

The aim of this study was to evaluate the diagnostic performance of SE, using RTE, for the assessment of liver fibrosis in multi-ethnic, urban patients in a European setting, with chronic liver disease using histology fibrosis staging (Ishak) as a reference standard.

Methods

Study population

We prospectively enrolled 98 adult patients with suspected chronic liver disease scheduled for liver biopsy or with confirmed (histological or clinical) cirrhosis in our institution over a one-year period (between October 2011 and October 2012). Inclusion criteria were age >18 years; suspected chronic liver disease based on clinical history, serum biochemistry, prior imaging or prior liver biopsy; referral for ultrasound and liver biopsy for staging and grading of fibrosis and/or cirrhosis. The cohort of patients with confirmed cirrhosis on imaging was not required to undergo further liver biopsy. Exclusion criteria included liver transplantation within the last six months, suspected or known acute liver disease and pregnancy. The study was performed following ethical approval (study and registration number: 11/LO/0552, KCH11-143), and informed consent was obtained from all participants.

Strain elastography

B-mode standard ultrasonography and SE measurements were performed prior to liver biopsy using a Hitachi HI VISION Preirus machine (Hitachi Medical Systems, Tokyo, Japan), with a EUP-L52 linear (3–8 MHz) transducer. Subjects were examined in a supine position with the right arm extended over the head by three trained observers (SV, JJ and OB). The transducer was placed in a right intercostal space and angled manually towards the heart (external compression source) without exerting any manual pressure with the transducer. The rectangular region of interest (ROI) of the hepatic parenchyma was 25 × 25 mm with the top of the ROI positioned approximately 10 mm inside the capsule of the liver to avoid multiple reflections and any large vessels (Figure 1).²⁰

Figure 1.

(a) Real-time tissue elastogram from a 27-year-old male with hepatitis B viral hepatitis which demonstrates relative “soft” liver texture. The histological fibrosis stage is Ishak 1. (b) Real-time tissue elastogram from a 63-year-old female with hepatitis C viral hepatitis which demonstrates relative “hard” liver texture. The histological fibrosis stage is Ishak 6.

The elastography module is based on real-time analysis of tissue displacement (strain) induced by dynamic cardiac movement of the ROI. A colour map is generated showing hard (blue), intermediate (green) and soft (red) tissue areas. The measurement area was chosen when the colour-coded elastogram was stable with any vessel or rib shadows minimized and recorded for 5 seconds. Patients were instructed to hold their breath (in a neutral phase) during imaging acquisition (at least five heart beats). The best image at negative peak strain on the strain graph was recorded when the image was subjectively most green and then most blue. The strain histogram was visualized, and analysis was performed in the ROI. Image acquisition and strain histogram measurements were repeated further two times. Digital images were stored at maximum quality and reviewed off-site by the ultrasound manufacturer. Image features were extracted from each elastography image.²¹ Multiple regression analyses were then performed with the following nine image features: (1) mean of relative strain value, (2) standard deviation of relative strain value deviation, (3) ratio of blue area in the analysed region, (4) complexity of blue area, (5) kurtosis of strain histogram, (6) skewness of strain histogram, (7) entropy, (8) inverse difference moment, and (9) angular second moment to calculate the LF Index using a previously described formula.²² The LF Index equation using these nine features was based on an equation adapted from Japanese patients with hepatitis C.^12,23 The mean value of the three LF Index measurements was used as the result. A higher LF Index indicates harder hepatic elasticity, and by inference more advanced liver fibrosis or cirrhosis.

Transient elastography

For logistical reasons, TE examinations (FibroScan®, Echosens, France) could not be performed on the same day as the liver biopsy; however, they were performed in all patients within three months of the liver biopsy using methods described previously,²⁴ by experienced observers as part of routine clinical practice. Measurements were performed on the right lobe of the liver through the right intercostal spaces. The medians of 10 measurements were recorded and the results expressed in kilopascals.

Serum fibrosis markers

Aspartate aminotransferase (AST), alanine aminotransferase, gamma glutamyl transferase, total bilirubin, platelet count, international normalized ratio (INR) and alkaline phosphatase were measured on the same day as the SE, and the aspartate aminotransferase-to-platelet ratio index (APRI)²⁵ and King’s Score²⁶ were then calculated. The APRI was calculated as: [(AST/upper limit of normal range)/platelet count (10⁹/L)] × 100.²⁵ The King’s Score was calculated as: age × AST × INR/platelet count (10⁹/L).²⁶

Liver histology

The histology specimens were taken on the same day following SE in the right lobe or from archived biopsy specimens in patients with documented cirrhosis. SE was performed before biopsy to avoid tissue disturbance due to the biopsy. All biopsies were performed percutaneously under ultrasound guidance using an 18-G Tru-Cut needle (Argon Medical Devices Inc., Athens, Texas). The biopsy specimens were fixed in formalin and embedded in paraffin according to standard procedures. All biopsy specimens were evaluated by a single experienced liver histopathologist (AQ) who was blinded to the patients’ clinical data and ultrasound measurements. Liver fibrosis stage was scored using the biopsy criteria described for the Ishak stage scoring systems.²⁷

Statistical analyses

Statistical analysis was performed using Statistical Packages for the Social Sciences (SPSS) for Windows (v22, IBM, Chicago) and MedCalc for windows, v17.6, All predictors for the stage of fibrosis (SE using LF Index, TE, King’s Score and APRI) are continuous variables and were therefore summarized as mean ± standard deviation or as medians and range. The diagnostic performances of these noninvasive tests for the prediction of fibrosis in each of the patients were then assessed by plotting the receiver-operator characteristic (ROC) curves. Optimal cut-off values were chosen to maximize the sum of the sensitivity and specificity using the Youden Index for different fibrosis thresholds: Ishak 0–2 vs. 3–6 (Ishak ≥3), Ishak 0–4 vs. 5–6 (Ishak ≥5). For this study, significant fibrosis was defined as Ishak stages 3 and above and severe fibrosis/cirrhosis, now termed advanced stage liver disease²⁸ as Ishak stage 5 or above. Diagnostic accuracy was also evaluated by comparing the sensitivity, specificity, positive and negative predictive values based on these cut-off values. The 95% confidence intervals were determined for the noninvasive markers and utilized when comparing the area under the ROC (AUROCs) curves. Differences between the AUROCs were compared by using a Delong test.²⁹ Spearman’s Correlation coefficient was calculated to test for the relationship between Ishak liver fibrosis stage and the noninvasive tests (SE, TE, King’s Score and APRI). Weak, moderate and strong correlations were defined for Spearman’s correlation coefficient values ρ < 0.4, 0.4 ≤ ρ < 0.59, and ρ ≥ 0.60, respectively. All tests were two sided and P < .05 signified a significant difference.

Results

Patient characteristics

Ninety-eight patients met the inclusion criteria and were enrolled in the study. Of these, 78 patients underwent liver biopsy; a further 20 patients with a confirmed clinical diagnosis of cirrhosis underwent B-mode standard ultrasonography and SE without further liver biopsy.

Relationship between LF Index, serum markers and liver biopsy histologic findings

Of the 98 enrolled patients, SE measurements were successful in 97 patients (success rate 98.98%). Twenty-four patients were excluded from this analysis because of unreliable clinical assessment of cirrhosis on repeat ultrasound (n = 6), no histology report due to inadequate samples (n = 2), SE measurement that could not be analysed (n = 16). This left 73 patients suitable for analysis. Their characteristics are summarized in Table 1. The patient ethnicity of the study cohort is as follows: 37.0% Caucasian (n = 27), 31.5% African-Caribbean (n = 23), 20.5% Asian (n = 15), 8.2% other (n = 6) and 2.7% mixed (n = 2). Most patients with chronic liver disease had hepatitis B (n = 52/73, 71.2%). The proportion of patients with significant (Ishak stage ≥3) and severe fibrosis/cirrhosis (Ishak stage ≥5) was 27.4% (n = 20/73) and 9.6% (n = 7/73), respectively. The median (minimum and maximum values) LF Index, APRI and King’s Score for each Ishak fibrosis stage are listed in Table 2 and displayed as box and whisker plot in Figure 2. There was weak significant correlation between fibrosis stage and the LF Index (Spearman’s ρ = 0.385; P = 0.001). There were moderate significant correlations between fibrosis stage and serum markers (APRI: Spearman’s ρ = 0.524, P < 0.001; King’s Score: Spearman’s ρ = 0.582, P < 0.001).

Figure 2.

Box and whisker plots of (a) LF Index, (b) TE, (c) APRI, and (d) King’s Score according to different Ishak fibrosis stage. The length of the box represents the interquartile ranges (second and third quartiles) in which 50% of the values are located. Circles or stars represent outliers. The thick line through each box represents the median value. The error bars show the minimum and maximum values (range). Open circles and stars represent outliers.

Table 1.

Demographic characteristic of the analysed patients.

Characteristic	Relationship between SE and liver histology (n = 73)	Relationship between SE, TE and liver histology (n = 52)
Gender n (%)
Male	42 (57.5)	31 (59.6)
Female	31 (42.5)	21 (40.4)
Age (years) (range)	40.4 ± 12.5 (20–69)	41.2 ± 12.0 (20–68)
Total bilirubin (µmol/L)^a	12 ± 5	12 ± 5
AST (U/L)^a	47 ± 42	51 ± 46
ALT (U/L)^a	58 ± 66 (n = 57)	60 ± 64 (n = 41)
GGT (U/L)^a	59 ± 101	68 ± 118
Alkaline phosphatase (U/L)^a	76 ± 29	76 ± 30
Platelets (10⁹/L)^a	219 ± 71	220 ± 76
INR (ratio)^a	1.02 ± 0.08	1.03 ± 0.09
King’s Score	11.8 ± 19.4	11.8 ± 19.4
APRI	0.25 ± 0.33	0.25 ± 0.33
Diagnosis, n (%)
Chronic hepatitis B	52 (71.2)	34 (65.4)
Chronic hepatitis C	16 (21.9)	15 (28.8)
Coinfection (B + D)	3 (4.1)	2 (3.8)
Other	2 (2.7)	1 (1.9)
Ishak fibrosis stage, n (%)
0	11 (15.1)	7 (13.5)
1	29 (39.7)	22 (42.3)
2	13 (17.8)	6 (11.5)
3	9 (12.3)	7 (13.5)
4	4 (5.5)	3 (5.8)
5	4 (5.5)	4 (7.7)
6	3 (4.1)	3 (5.8)

Data are presented as mean value ± standard deviation unless stated. AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: gamma-glutamyl transferase; INR: international normalized ratio; APRI: AST-to-platelet ratio index.

Determination at screening phase before ultrasound.

Table 2.

Median value and range (in brackets) of each parameter in each Ishak fibrosis stage group and their correlation coefficient with Ishak fibrosis stages.

Diagnostic test	Ishak fibrosis Stages							Correlations (P value)
Diagnostic test	Stage 0	Stage 1	Stage 2	Stage 3	Stage 4	Stage 5	Stage 6	Correlations (P value)
LF Index	1.71 (0.64–2.26)	1.72 (1.18–2.50)	1.70 (0.94–2.30)	2.11 (1.40–3.64)	2.05 (1.57–3.68)	2.10 (2.05–2.52)	2.37 (1.91–2.50)	ρ = 0.385 (P = 0.001)
TE	5.4 (3.9–7.1)	5.5 (3.3–10.3)	7.0 (5.6–10.5)	8.8 (4.4–11.1)	13.9 (10.3–25.7)	10.9 (9.6–12.0)	26.3 (16.9–36.9)	ρ = 0.675 (P = 0.001)
APRI	0.12 (0.06–0.46)	0.12 (0.05–0.26)	0.14 (0.07–0.34)	0.18 (0.09–1.74)	0.65 (0.49–1.01)	0.55 (0.35–0.68)	0.77 (0.22–1.54)	ρ = 0.524 (P < 0.001)
King’s Score	4.5 (2.8–12.5)	4.2 (1.6–9.5)	5.8 (2.2–14.2)	7.4 (4.4–66.0)	40.7 (26.5–55.7)	25.3 (19.8–29.5)	49.8 (8.9–109.9)	ρ = 0.582 (P < 0.001)

TE: transient elastography; APRI: aspartate aminotransferase-to-platelet ratio.

Relationship between TE and liver fibrosis scores

A further 21 patients were excluded from this analysis due to lack of TE measurements, leaving 52 patients suitable for analysis. Their characteristics are summarized in Table 1. The TE measured in the study patients ranged from 3.3 KPa to 36.9 KPa. The median (minimum and maximum value) TE value for each Ishak fibrosis stage is listed in Table 2 and Figure 2. There was strong significant correlation between fibrosis stage and the TE measurement (Spearman’s ρ = 0.675; P = 0.001).

Diagnostic accuracy of LF Index, TE and serum markers using Ishak histological scores

The accuracy of SE (using LF Index), TE, APRI and King’s Score in predicting significant (Ishak ≥ 3) and severe (Ishak ≥ 5) liver fibrosis is shown in Table 3 and Figure 3.

Figure 3.

Comparison of the receiver operating characteristic curves of noninvasive methods for diagnosis of (a) significant fibrosis (Ishak ≥ stage 3) and (b) severe fibrosis/cirrhosis (Ishak ≥ stage 5) in patients with chronic liver disease in the study population.

Table 3.

Diagnostic performance of SE, TE and fibrosis serum markers (King’s Score, APRI) for determination of significant and severe fibrosis/cirrhosis according to Ishak score classification.

Parameter	Significant fibrosis (Ishak stage ≥ 3)				Severe fibrosis/cirrhosis (Ishak stage ≥ 5)
Parameter	LF Index	TE	APRI	King’s Score	LF Index	TE	APRI	King’s Score
AUROC (95% CI)	0.79 (0.68–0.88)	0.87 (0.75–0.95)	0.86 (0.76–0.93)	0.85 (0.74–0.92)	0.83 (0.73–0.91)	0.94 (0.84–0.99)	0.92 (0.84–0.97)	0.92 (0.84–0.97)
P value	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001	<0.0001
Optimal cut-off	1.87	8.3	0.18	8.77	2.07	9.4	0.22	8.77
Sensitivity (%)	85.0	82.35	80.00	70.00	71.43	100.00	100.00	100.00
Specificity (%)	73.5	85.71	83.02	90.57	75.76	84.44	78.79	81.82
+LR (%)	3.22	5.76	4.71	7.42	2.36	6.43	4.71	5.50
−LR (%)	0.20	0.21	0.24	0.33	0.57	0.00	0.00	0.00

These ROC curves were devised for the detection of significant fibrosis and severe fibrosis/cirrhosis. TE: transient elastography; AUC: area under receiver operating characteristic curve; APRI: aspartate aminotransferase-to-platelet ratio index; PPV: positive predictive value; NPV: negative predictive value.

The AUROCs of LF Index, SE, TE, APRI and King’s Score for diagnosis of significant fibrosis did not differ significantly (P > 0.05) (Figure 3(a)). Comparison of the AUROCs of SE (using LF Index), TE, APRI and King’s Score for the diagnosis of severe fibrosis/cirrhosis showed that TE had significantly higher accuracy compared to SE (using LF Index), P = 0.0149. No significant differences were detected when comparing AUROC between the other parameters (Figure 3(b)).

Discussion

Recent interest in noninvasive evaluation of liver disease is related to the risk of complications associated with liver biopsy and technical limitations of the procedure.³⁰ In view of this, various noninvasive methods have been developed to predict the presence of clinically significant fibrosis. In this study, we evaluated the use of LF Index calculated by SE in predicting the presence of significant liver fibrosis using liver biopsy as a reference standard. The principle finding of this study was that LF Index by SE was not a useful predicator of histologic fibrosis stages as determined by the Ishak scores. Secondary analyses showed that the diagnostic performance of SE in this heterogeneous population including predominant Caucasian and African-Caribbean patients was similar to other noninvasive tests for the assessment of significant liver fibrosis but inferior to TE for the assessment of severe fibrosis/cirrhosis in patients with suspected chronic liver disease.

A number of studies have evaluated the diagnostic performance of SE using RTE for the assessment of liver fibrosis in patients with chronic liver disease. Since RTE is essentially a qualitative technique, various semi-quantitative methods have been developed to analyse the elastograms produced by SE.⁸ These include the elasticity index,^14,31 the elasticity ratio^15,16,32 and the LF Index.^{12,21–23,33,34} The elastic ratio refers to the ratio of these values in the hepatic parenchyma to the values in a reference tissue such as intercostal muscles and intrahepatic venous vessels. The elastic index, elasticity score and LF Index are all calculated by formulas including several descriptive statistics (e.g. mean, median, maximum) derived from quantified pixel data. In this study, the LF Index was used as the analytic method of SE. It was the first quantitative method developed involving use of nine parameters.²¹ A meta-analysis of five studies (722 subjects) in 2014 showed significant heterogeneity when using the LF Index for the assessment of significant fibrosis, thereby limiting an assessment of the overall accuracy of RTE. The authors reported that RTE showed limited potential as a substitute for TE in the assessment of liver fibrosis.³⁵ A further meta-analysis in 2015 of 15 studies (1626 subjects) reported that the overall accuracy of RTE was nearly identical to TE for the evaluation of significant fibrosis but less accurate for the evaluation of cirrhosis.³⁶ The variable results reported with the different quantitative methods have therefore limited the clinical use of RTE.³⁵ There are, however, conflicting results to the 2015 meta-analysis whereby RTE was shown to have a strong positive correlation with histologic liver fibrosis and high diagnostic accuracy in predicting significant and severe fibrosis.^17,22,37 We postulate that the observed difference in diagnostic accuracy may be because prior studies were exclusively performed in East Asian populations where the body mass index is lower than in our study population, although this could not be analysed formally as body mass index from our study cohort was not collected at the time of the study.

The two endpoints used in this study were significant fibrosis (Ishak stage 3 or greater), which is an indication for anti-viral treatment in patients with chronic hepatitis B and C, and severe fibrosis/cirrhosis (Ishak stage 5 or greater), which leads to closer monitoring of complications: portal hypertension, hepatic insufficiency and hepatocellular carcinoma.³⁸ We used these liver fibrosis categories as they enable reliable identification of liver cirrhosis, as well as the ability to distinguish low risk of fibrosis (Ishak 0–2) from more advanced stages of liver fibrosis (Ishak 3–6). We evaluated the use of SE with liver histology using the seven-point Ishak staging systems which allows a more detailed description of advanced stage liver disease (stages 5 and 6) compared with the Metavir score. It has been argued that the gap between 3 (numerous septa without cirrhosis) and 4 (cirrhosis) in the Metavir score is too large and an additional level is required to differentiate between severe fibrosis and cirrhosis.³⁹

The strength of this study is that it not only compares the diagnostic accuracy of SE with the reference standard, liver biopsy, but also with TE and serum markers. TE was used as a comparative method of measuring liver stiffness in this study and it demonstrated AUROC values consistent with findings reported in meta-analyses for predicting significant fibrosis (F ≥ 2, AUROC = 0.88) and severe fibrosis (F ≥ 3, AUROC = 0.91).⁴⁰ A limited number of studies have compared the diagnostic accuracy of LF Index and serum fibrosis markers.

Limitations exist with our study. First, this was an unblinded study performed in a wide group of unselected patients with varying aetiologies of chronic liver disease, introducing possible bias due to histologic differences of the varying aetiologies of liver disease. However, most patients (>90%) had chronic viral hepatitis B or C. Further multicentre studies of larger patient cohorts using a similar study design are needed to establish optimal cut-off values for each fibrosis stage and aetiology. Second, the distribution of patients in our study was not equal through Ishak scores. We enrolled consecutive patients undergoing liver biopsy and the underlying distribution of patients reflects that normally observed in clinical practice. Finally, the same operators were used in the study and there was no patient control group. However, whilst each operator was aware that the patient had fibrosis, they were blinded to the pathological stage of the patient.

In conclusion, the diagnostic performance of SE using RTE in this population was similar to other noninvasive tests for the assessment of significant liver fibrosis but inferior to TE in the assessment of severe fibrosis/cirrhosis in patients with suspected chronic liver disease.

Footnotes

Acknowledgements

We would like to thank Akiko Tonomura and Tsuyoshi Mitake (Hitachi, Tokyo, Japan) for their support in performing the statistical analyses. We thank Ellison Bibby (Hitachi, UK) for her advice and technical support.

Contributors

All authors contributed equally to this work.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics Approval

Study and registration number: 11/LO/0552, KCH11-143; R&D Department, King’s College Hospital, Denmark Hill, SE5 9RS.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Guarantor

Paul S Sidhu and Cheng Fang.

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