A Primer to the Diagnostic and Clinical Utility of Spleen Stiffness Measurement in Patients With Chronic Liver Disease

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Abbreviations

ARFI

acoustic radiation force impulse imaging

AUROC

area under the receiver operating curve

BMI

body mass index

cACLD

compensated advanced chronic liver disease

CLD

chronic liver disease

CSPH

clinically significant portal hypertension

EGD

esophagogastroduodenoscopy

EV

esophageal varices

FDA

US Food and Drug Administration

HBV

hepatitis B

HCC

hepatocellular carcinoma

HCV

hepatitis C

HVPG

hepatic venous pressure gradient

LSM

liver stiffness measurement

MRE

magnetic resonance elastography

NPV

negative predictive value

NSBB

nonselective β‐blocker

PH

portal hypertension

PPV

positive predictive value

RTE

real‐time tissue elastography

SSM

spleen stiffness measurement

SWE

shear wave elastography

TIPS

transjugular intrahepatic portosystemic shunt

VCTE

vibration‐controlled transient elastography

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Patients with chronic liver disease (CLD) may present with varying severities of liver fibrosis. Fortunately, noninvasive testing with liver elastography is now widely available. It has changed our approach to staging liver disease, providing an opportunity to detect the presence of compensated advanced CLD (cACLD). ¹ , ² Nevertheless, noninvasive prognosis in cACLD, particularly those with cirrhosis and portal hypertension (PH), remains imperfect. For example, the rate of decompensation (variceal bleed, hepatic encephalopathy, or ascites) in patients with NASH cirrhosis varied significantly from 3% to 19% in two recent phase 3 trials. ³ , ⁴ This observation indicates that new tools are needed to improve the prediction of clinical progression from a compensated to decompensated state in cACLD.

Spleen stiffness measurement (SSM) is an emerging tool in our arsenal for predicting liver‐related outcomes. It is well established that PH leads to spleen tissue hyperplasia, which manifests as splenomegaly and hypersplenism, making spleen stiffness a good predictor of clinically significant PH (CSPH; Fig. 1). ⁵ In the recent past, various elastography techniques have been used to assess spleen stiffness. ⁶ , ⁷ , ⁸ , ⁹ More recently, FibroScan 630 Expert was cleared by The United States Food and Drug Administration and is the first and only device that can measure both liver stiffness measurement (LSM) and SSM, in addition to controlled attenuation parameter. We anticipate that this tool will be widely used by clinicians who are taking care of patients with cACLD. Given that SSM is now feasible in the United States, we aim to (1) present different methods to evaluate spleen stiffness, (2) summarize the performance of different SSM techniques in predicting CSPH or indicating the presence of large esophageal varices (EVs), and (3) provide guidance on the implementation of SSM in clinical practice.

FIG 1.

Spleen stiffness in the natural history of cirrhosis. As PH increases risk for liver‐related complications, there is a parallel increase of spleen stiffness.

SSM Techniques

Figure 2 summarizes the various methods that are currently available internationally for SSM. The techniques, their advantages, and their limitations are described in this section. In addition, Table 1 provides a detailed comparison of each technique and their predictive performance. An essential step in SSM by ultrasound‐based elastography is to first locate the spleen, which often requires two separate devices. This step is not necessary for LSM.

FIG 2.

Various methods currently available for SSM. There are four major ways to complete SSM, each with its own advantages and disadvantages, which are summarized in this figure. Clock symbol, the time required; wave symbol, frequency on the waves; ↓, depth of the tissue that is measured, ranges of possible stiffness measurement scores; green checkmark, characteristic of technique; red X, not a characteristic.

TABLE 1.

Comparison of Different SSM Techniques and Their Predictive Performance

*The references listed in this table can be found in the Supporting information.

Two‐Dimensional Shear Wave Elastography

Two‐dimensional shear wave elastography (SWE) is a quantitative ultrasound‐based technique that uses the propagation of shear waves in real time to measure LSM and SSM. ⁸ SWE has several advantages, such as adding the technology to existing ultrasound machines, actively visualizing the organ of interest, and choosing the location within the visual field for measurement. Furthermore, SWE produces waves that travel deeper into the tissue allowing for SSM even in those with ascites. ⁸ Small spleen size, obesity, gastrointestinal gas, and patient’s ability to breath‐hold can limit success in obtaining valid measurements using SWE. ¹⁰

Magnetic Resonance Elastography

Magnetic resonance elastography (MRE) is a quantitative imaging method that can assess tissue stiffness by spreading shear waves through parenchymal tissue, including the liver and spleen. ⁶ Compared with other SSM techniques, the technical failure rate is low for MRE in obese patients and patients with ascites. It allows for the assessment of the abdominal organs beyond stiffness measurement. ¹¹ Despite these advantages, MRE has lower performance when detecting early to intermediate stages of fibrosis and does not provide real‐time results, thus requiring formal interpretation by a radiologist. ¹² , ¹³ It is also the costliest modality for SSM. However, greater cost‐effectiveness may be achieved if MRE for LSM and SSM is combined with MRIs performed to evaluate cirrhosis and hepatocellular carcinoma (HCC). ¹¹

Acoustic Radiation Force Impulse Imaging

Acoustic radiation force impulse imaging (ARFI) is another quantitative ultrasound method to measure LSM and SSM. ⁷ This imaging technique uses short‐duration acoustic pulses that create shear waves with the wave velocity predicting tissue stiffness. ¹⁴ As with SWE, the advantages of ARFI are that it can be implemented in ultrasound machines currently used in practice, and it allows the operator to choose a region of interest, albeit smaller than SWE. The greatest limitation of ARFI is that it has a narrow range of values, making it challenging to provide clinically significant cutoffs in different diseases. ¹⁵ , ¹⁶ Another limitation is the longer completion time compared with other shear wave–based tools.

Real‐Time Tissue Elastography

Real‐time tissue elastography (RTE) is a qualitative ultrasound‐based method measuring spleen elasticity. As a qualitative method, RTE cannot be compared with quantitative methods such as MRE, TE, and SWE. Advantages are that it is quick, inexpensive, and does not require a dedicated system. Major disadvantages are the limited evidence base for its use and qualitative results (stiffness present versus not). ⁹

Vibration‐Controlled Transient Elastography

Vibration‐controlled transient elastography (VCTE) is another quantitative shear wave–based method for measuring liver and spleen stiffness. FibroScan is a device using VCTE to predict the level of liver fibrosis successfully and is validated in diverse populations and liver disorders. In the United States, the FibroScan 630 Expert, the newest version of FibroScan, can measure spleen and liver stiffness using a probe that can produce a 50‐Hz wave for LSM, as well as a 100‐Hz wave specially for SSM (Fig. 3). ¹⁷ It also comes with an ultrasound probe allowing for easier localization of the spleen and providing more accurate measurements. ¹⁷ FibroScan is widely used for LSM because it is a portable machine; the software is user friendly and allows for quick, in‐office measurement of LSM providing real‐time results. ¹⁵ , ¹⁶ Limitations of VCTE are the requirement of a dedicated device and an operator’s inability to choose the region of interest. ¹⁵ , ¹⁸ Another limitation of VCTE‐based SSM is higher failure rates in small‐diameter spleens. FibroScan 630 Expert currently has only an M probe dedicated to SSM, leading to a higher failure rate in obese patients or those with ascites. ¹⁷

FIG 3.

Steps involved in VCTE measurement. SSM is accomplished by various techniques, including VCTE after it is located using ultrasound probe.

Clinical Use of SSM

Determining the Presence of CSPH and EVs

Currently, the gold standard for defining CSPH is hepatic venous pressure gradient (HVPG) measurement or esophagogastroduodenoscopy (EGD) to detect the presence of varices. Measurement of the HVPG is invasive and costly. ¹⁹ Furthermore, although LSM and platelet count serve as good noninvasive predictors of CSPH, correlation with severity is lost when HVPG is >10 mm Hg, leading to underestimating CSPH and decompensation. ¹⁷ For example, Vermehren et al. ⁷ showed that using ARFI, SSM is more accurate than LSM in predicting large EVs. Similarly, SSM was the only parameter that correlated with the size of EV in a study that assessed various noninvasive makers, including platelet count, splenic diameter, portal vein diameter, aspartate aminotransferase, and LSM. ²⁰ Finally, Stefanescu et al. ¹⁷ showed that significantly more endoscopies were avoided when SSM assessed by FibroScan 630 Expert was added to Baveno VI criteria when ruling out high‐risk EVs. Table 1 summarizes the performance of SSM in predicting HVPG and the presence of EVs in the current literature.

Assessing Treatment Response for CSPH

Nonselective β‐blockers (NSBBs) represent an effective therapy of choice primary prophylaxis for high‐risk EVs. The gold standard for predicting the response to NSBBs is HVPG, with a goal reduction of ≥10% from baseline or ≤12 mm Hg. It has been shown that an SSM decline greater than 10% in response to prophylactic carvedilol successfully predicts a change in HVPG after 3 months of NSBB therapy (100% sensitivity and 60% specificity) in those with high‐risk EV. In contrast, LSM did not show a correlation with a change in HVPG. ²¹ , ²² It has been shown that patients are protected from EV bleeding with decrease of HVPG to less than 12 mm Hg. ²³ To our knowledge, no studies assessed SSM correlation with high‐risk EVs improvement on EGD.

Transjugular intrahepatic portosystemic shunt (TIPS) is another method for reducing portal pressures. TIPS failure can be seen in asymptomatic patients. Therefore, TIPS patency is monitored with color Doppler sonography to measure flow velocity rates in different anatomic locations of the shunt. SSM was positively correlated with the lowering of HVPG after the TIPS procedure (r² = 0.7238, P < 0.001), whereas LSM did not show a correlation. ²⁴

Furthermore, SSM can also be used to evaluate HVPG changes after liver transplantation. SSM levels rapidly decline 2 weeks after transplantation and with later gradual decreases in SSM in the next 2 to 6 weeks. ²⁵ Given this response, SSM can be used in outpatient monitoring of post‐liver transplant individuals to evaluate disease progression and predict decompensation similar to pre‐liver transplant individuals.

Emerging Roles for SSM

In those with HCC, SSM can play a role in predicting recurrence. In one study, SSM measured by FibroScan 50‐Hz probe was associated with late HCC recurrence (>24 months since resection) independent of traditional clinical and pathological predictors of HCC recurrence. ²⁶

SSM may also play an important role in monitoring patients with chronic hepatitis B (HBV) and hepatitis C (HCV) because it correlates with portal inflammation better than LSM does. One study showed that SSM was significantly higher in patients with chronic HCV and HBV without liver fibrosis than in healthy control subjects. Another study showed that SSM was higher in people with chronic HCV and portal inflammation than in those with alcoholic liver disease and lobular inflammation. Together, these studies indicate that changes in SSM occur early in diseases associated with portal inflammation and before significant liver fibrosis develops, thus providing an opportunity for earlier risk stratification. ²⁷ , ²⁸

Conclusion

Performance of SSM in several clinical scenarios shows that SSM is an important tool for managing those with cACLD. Unfortunately, previously published studies used various SSM techniques and probes, leading to diverse datasets with different cutoffs. The literature is challenging to navigate for clinicians who are just getting familiar with this space. Because SSM is anticipated to join the tools used in routine hepatology practice, we summarized these data to improve the clinical applicability of SSM. With US Food and Drug Administration (FDA) approval of the first device able to measure SS, we anticipate future studies will strengthen the correlation between SSM, presence of PH, response to treatment, and monitoring of those with CLD, while also providing data on cost utility. In the United States, successful incorporation of SSM into everyday clinical practice requires further studies to address reliability, interobserver and intraobserver variability, and minimum operator experience. Furthermore, validated cutoff values for the FibroScan 630 Expert using the 100‐Hz probe are necessary before making clinically actionable decisions.

Supporting information

Supplementary Material