Elastography Assessment of Liver Fibrosis

Elastography was validated by comparing liver stiffness (LS) results to the amount of fibrosis found on biopsy. According to histological staging, four different ranges of LS were defined as surrogate markers of fibrosis (F0/F1 no or low‐grade fibrosis, F2 moderate fibrosis, F3 severe fibrosis, and F4 cirrhosis). However, the diagnostic accuracy of elastography is higher in identifying no or minimal fibrosis (F0/F1), severe fibrosis or cirrhosis (F3–F4), and in general in ‘ruling in’ and ‘ruling out’ cirrhosis. The intermediate ranges of LS correlate with a continuum of moderate to severe fibrosis, in which there could be a certain degree of overlap, especially if one considers that the fibrosis scoring system traditionally follows a scale of descriptive ‘semiquantitative’ measurements, while LS is a quantitative method (Figure 9.2.1). Hence, when stiffness values fall in this ‘grey zone’ particular caution is recommended, suggesting additional tests and eventually even liver biopsy in case of ongoing diagnostic uncertainty [6].

The interpretation of LS results needs to take several elements into account:

• Equipment‐related variability: there are several available elastographic techniques and manufacturers, for which LS measurements and fibrosis cut‐off values are different and therefore they must not be considered interchangeable [7]. For example, the stiffness values that correlate with moderate or severe fibrosis measured by a specific software could instead relate to minimal and moderate fibrosis, respectively, obtained with another software. Therefore the report should always specify which technique and equipment were used. However, while a difference in stiffness ranges of fibrosis is found among different kinds of software, all elastographic techniques agree that a stiffness value <5 kPa will surely exclude fibrosis, if the reliability criteria are satisfied. With regard to cirrhosis, all systems are highly accurate in distinguishing no fibrosis from severe fibrosis/cirrhosis, although variability of cut‐off values is not only related to the elastographic software, but also to aetiology and confounding factors [7].
  
• Liver disease aetiology: it is extremely important to acknowledge differences in aetiology‐related liver disease. In fact, although the endpoint of CLD is cirrhosis, the timing and natural history might be different, depending on the kind of inflammatory process, distribution of fibrosis, and development of PH, as well as the malignant potential. One of the issues in using different systems is that not all of them have been validated against biopsy or in all liver disease aetiologies, advising caution, integration, and careful interpretation of the results.
  
• Confounding factors: as previously mentioned, LS is relative to the biomechanical properties of liver parenchyma, therefore a higher measurement should not be considered an absolute value attributable solely to fibrosis. This is a very important point when interpreting elastography results, since hepatic congestion, cholestasis, inflammation, and parenchymal infiltration can all increase stiffness, regardless of fibrosis through different mechanisms [1]. Under these circumstances, elastography can yield false‐positive results when fibrosis is not even present or overestimate the severity of underlying liver disease (Figure 9.2.2). Along these lines, it can be very difficult and sometimes impossible to evaluate the presence or severity of liver disease in relation to fibrosis. Integration with clinical/laboratory investigations, background history, and ultrasound findings provides the necessary information to evaluate the presence or absence of superimposed elements. The clinical response to dynamic changes and delta stiffness value during a specific treatment (antiviral treatment, diuretics, immune suppression, biliary obstruction resolution, alcohol withdrawal) might be of help, although caution and strict follow‐up are highly recommended (Figures 9.2.3–9.2.5) (Videos 9.2.1 and 9.2.2). 

Elastography Assessment of Portal Hypertension

PH is a crucial clinical landmark in the natural history of liver disease, representing the physiopathological base of cirrhosis‐related complications [8]. Therefore once CLD is diagnosed, it is extremely important to know if the patient has cirrhosis and if the threshold of clinically significant portal hypertension (CSPH) is reached. However, it is also important to bear in mind that the timeframe between these two endpoints is difficult to define, that imaging is usually unable to assess the degree of PH, and that liver disease might clinically declare itself with a decompensating event (variceal bleeding, ascites, hepatic encephalopathy) if its severity is not predicted accurately. It is within this physiopathological landscape that elastography fills a gap of diagnostic uncertainty, in which imaging might underestimate the severity of liver disease, and in which the diagnostic gold standard would be highly invasive (hepatic venous pressure gradient [HVPG] measurement) and endoscopic screening could be carried out unnecessarily, in the absence of high‐risk varices. Robust data shows that liver elastography is able to predict the presence of both CSPH and high‐risk varices in cirrhosis with considerably high accuracy, reducing the number of unnecessary endoscopies [9, 10]. Nevertheless, a few considerations need to be kept in mind.

Physiopathological Background of Cirrhotic Portal Hypertension and Non‐invasive Assessment

The development of PH can be roughly distinguished in a first phase characterised by liver fibrosis and nodular regeneration, which increase intrahepatic resistances, and in a second phase related to more advanced cirrhosis, in which extrahepatic factors, mainly vasoactive molecules, influence splanchnic flow, further increasing PH.

LS has a good linear correlation with HVPG until the threshold of CSPH is reached (HVPG ≥10 mmHg). Since varices develop in the presence of severe PH, with a relative increase of bleeding risk for HVPG >12 mmHg, the diagnostic accuracy of LS per se, in detecting high‐risk varices, is lower than expected [11]. The accuracy of non‐invasive assessment of PH was improved by combining LS and platelet count, as recommended by the Baveno VI Consensus Conference (and confirmed in Baveno VII), which initially proposed a vibration‐controlled transient elastography (VCTE) LS cut‐off ≤20 kPa and a platelet count ≥150 000/mm³ to rule out patients without high‐risk varices, hence who could safely avoid an endoscopic screening. These recommendations have been validated extensively with VCTE in hepatitis B (HBV) and hepatitis C (HCV)‐related cirrhosis, as well as in alcohol‐related cirrhosis, with the prerequisite of the absence of superimposed alcoholic hepatitis [9, 10]. However, even better results were obtained by measuring spleen stiffness (SS), which proved to be independently correlated to CSPH, accurately predicting the presence of high‐risk varices as well as the risk of clinical decompensation in cirrhosis [12, 13]. In other terms, when the threshold of CSPH is reached significant variability can be found among LS values, although the integration with platelet count increases the diagnostic accuracy of diagnosing CSPH. Nevertheless, SS has a stronger, progressive, and independent correlation with the severity of PH (Figure 9.2.6). The rationale behind the higher accuracy of SS compared to LS in predicting severe PH is thought to be secondary to the following reasons:

• While PH develops, the resistance to blood flow is transmitted through the splenic vein to the splenic parenchyma, which becomes highly congested, with a consequent increase in intrasplenic pressure and therefore SS.
  
• The more advanced cirrhosis is, the more nodular, fibrotic, and irregular hepatic parenchyma will be. Such irregularities can influence LS values, yielding high results or relatively low ones, regardless of the severity of CLD, since measurements might be taken on large regenerative nodularities or areas of scarring (Figure 9.2.7) [7]. SS instead seems to have a more homogeneous distribution of stiffness throughout splenic parenchyma (Figure 9.2.8), likely because the increase of SS in PH is mainly secondary to congestion, as shown by its significant reduction after transjugular portal‐systemic shunt placement and even more after liver transplantation [14].
  
• The severity of PH in advanced stages of cirrhosis is less dependent on hepatic structure and more on extrahepatic factors [13, 15]. In addition, SS has proven to be an independent marker of PH, regardless of the underlying cause [2]. This is clinically very relevant, because it permits the distinction of non‐cirrhotic PH in which LS, even in the presence of severe PH, is usually relatively lower compared to cirrhosis (Figure 9.2.9) [16]. In addition, SS would be very useful in evaluating the presence of CSPH in different liver disease aetiologies, where a presinusoidal component might be present, such as in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), and in which PH could develop prior to advanced cirrhosis. Finally, SS could provide key information in those cases in which confounding factors influence LS reliability, making it an important discriminant for ‘ruling in’ or ‘ruling out’ the presence of CSPH.

Non‐invasive Liver Disease Assessment and the Importance of Integrating Elastography with Ultrasound Imaging

Ultrasound can detect parenchymal changes of CLD expressed as echotexture heterogeneity and irregular outline. In general, its specificity is high for advanced stages of CLD, where clear modification of liver morphology, signs of PH, and clinical decompensation are more obvious, but its sensitivity is low, especially in the pre‐cirrhotic and early stages of cirrhosis.

However, it is of note that despite the severity of liver disease, underlying aetiology might influence liver appearance, sometimes showing pronounced parenchymal heterogeneity in pre‐cirrhosis, or a relatively smooth outline and homogeneous echotexture when cirrhosis is already established. Similarly, ultrasound cannot establish the degree of PH unless clear signs of its presence can be seen, such as portal venous flow inversion and portal‐systemic vascular collaterals. In fact, even in the presence of splenomegaly, dilated portal vein, and morphological changes, which suggest advanced cirrhosis, the chance of significant PH is high, but the accuracy of staging it is insufficient. On the other hand, ultrasound is extremely useful for revealing features that suggest the diagnosis of non‐cirrhotic PH, such as portal vein thrombosis, periportal fibrosis, or rarer causes associated to haematological malignancies or parasitic infections. Therefore, while ultrasound is fundamental for revealing liver appearance, spleen size, and splanchnic circulation, elastography is able to overcome imaging limitations by objectively estimating both fibrosis and PH. The most accurate results of non‐invasive assessment therefore require the integration of both ultrasound and elastography (Figures 9.2.10–9.2.16).