Personalized management of cirrhosis by non-invasive tests of liver fibrosis

Serum tests

The advantages of serum tests include high applicability (successful measurements can be made in most cases) and relatively simple logistics. Doctors may obtain blood samples at their clinics and send them to designated laboratories even for more specific biomarkers. Serum tests can be divided into class I biomarkers and class II biomarkers. Class I biomarkers specifically measure the activity of fibrogenesis or fibrinolysis. In contrast, class II biomarkers do not measure fibrosis directly but represent parameters that correlate with fibrosis. For example, aspartate aminotransferase (AST) is a marker of hepatic necroinflammation and not fibrosis. However, patients with fibrosis and cirrhosis often have increased AST levels. Although class I biomarkers are expected to directly reflect fibrosis and be more accurate than class II biomarkers, this has not been consistently demonstrated in prospective studies.

In any case, at present there is no single marker that can adequately reflect fibrosis. Therefore, in most situations several biomarkers or a combination of biomarkers and other clinical features are used. Some of the combined panels such as FibroTest, FibroMeter and enhanced liver fibrosis (ELF) score have been commercialized. It should be noted that such combined tests are modeled against liver histology, which is an imperfect reference standard. In other words, even if the models can 100% faithfully reflect liver histology, the accuracy of liver histology to diagnose fibrosis and cirrhosis will be the ceiling of accuracy of the new models.10

Some of the class II biomarkers are more generic. Examples include the AST-to-alanine aminotransferase (ALT) ratio and the AST-to-platelet ratio index (APRI). In other cases, owing to the pathophysiology of different liver diseases, the class II biomarkers are more disease-specific. For instance, metabolic factors are overrepresented in the NAFLD fibrosis score, which should only be applied in patients with NAFLD.1112

Physical measurements

The other main class of non-invasive tests of liver fibrosis relies on physical measurement of liver stiffness and elasticity. Although the cutoffs of the measurements are determined with reference to histology, these tests are not modeled against histology and theoretically may achieve better prediction than histology. In fact, studies in patients with chronic viral hepatitis suggest that transient elastography may be better than histology in predicting overall mortality.1314

Transient elastography by FibroScan (Echosens, Paris, France) is currently the most commonly used method to measure liver stiffness.15 It estimates liver fibrosis by measuring the velocity of a shear wave in the liver parenchyma. This is based on the physical principle that waves travel faster in a stiffer medium. The main advantage of transient elastography is the ease of use and high reproducibility.16 Compared with serum tests, transient elastography is less applicable in obese patients, although the new XL probe partially compensates for that.17 Liver stiffness is also affected by high ALT level, hepatic congestion, food intake and amyloidosis. Because the correlation between liver stiffness and fibrosis is a generic phenomenon, the technique can be applied to patients with different liver diseases, though the appropriate cutoffs are higher in patients with alcoholic liver disease.18

Newer techniques such as acoustic radiation force impulse and shear-wave elastography allow simultaneous visualization of the liver parenchyma and measurement of liver elasticity.1920 This can thus combine HCC surveillance and liver fibrosis assessment in a single examination. Magnetic resonance elastography appears to be highly accurate and is not affected by obesity, but machine availability and the costs of examination can be prohibitive.21 These new techniques also have not been as extensively validated as transient elastography.

For simplicity, doctors usually adopt one or more recommended cutoff values in the interpretation of any of the non-invasive tests above. In reality, however, the more extreme the values of the non-invasive tests are, the more we are confident in whether a patient has fibrosis/cirrhosis or not. For example, a probability-based interpretation of liver stiffness measurements (LSM) has been proposed.22 Based on the exact LSM, the probability of a patient having different fibrosis stages can be determined. The complexity of this approach limits its use in real life practice. Nonetheless, as a patient is more likely to have cirrhosis and advanced cirrhosis when he has more extreme non-invasive tests results, this forms the basis of extending the tests to stratify the risk and predict complications in cirrhotic patients.

Current recommendations and unmet need

HCC is one of the most important complications in patients with chronic liver diseases.23 HCC surveillance is an indispensable part of the management of liver patients. The current Asian Pacific guidelines recommend 6-monthly trans-abdominal ultrasonography and serum alpha-fetoprotein (AFP) testing for HCC surveillance.24 Despite the fact that AFP has been widely adopted for decades, it has been criticized as neither sensitive nor specific.25 Hence the latest American guidelines stopped recommending the use of AFP in the surveillance program.26 Nonetheless, a recent study demonstrated a satisfactory sensitivity and specificity of AFP for HCC in CHB patients received antiviral therapy.27 Therefore some experts believed that the calls for abandoning the monitoring of AFP levels might be premature, especially given the already low HCC surveillance rate in developing countries and at primary care settings.28

HCC surveillance improves the prognosis of patients by identifying tumors of smaller sizes, fewer numbers of tumors, and longer overall survival.29 Unfortunately, the 5-year mortality rate was still close to 40% despite the regular HCC surveillance. This observation points towards the fact that the current HCC surveillance recommendation is still far from satisfactory.

The key components of an optimal surveillance program include accurate risk stratification and reliable surveillance tools. Hence there is a need for accurate HCC risk prediction to assist prognostication as well as decision on the need for HCC surveillance.

Non-invasive tests and HCC risk

HCC risk score based on non-invasive tests

The risk factors of HCC in patients with chronic hepatitis B are well known, and various groups have derived HCC risk scores based on the factors.37 Since cirrhosis is the single most important risk factor for HCC development, non-invasive tests of fibrosis may improve prediction by not only diagnosing cirrhosis more accurately but also reflecting the severity of cirrhosis. To further consolidate the important role of LSM on HCC risk prediction, it was incorporated into a risk score for HBV-related HCC, called LSM-HCC score, together with three other important clinical parameters namely age, serum albumin and HBV DNA level.38 LSM has replaced clinical cirrhosis, the heavily weighed component in the original CU-HCC score,39 in order to provide more objective and accurate diagnosis of cirrhosis (Table 1). This new LSM-HCC score excludes future HCC with high negative predictive value (99.4-100%) at 5 years.38

Table 1.

CU-HCC score vs. LSM-HCC score [Modified from reference Wong VW et al. JCO 2010 & Wong GL et al. J Hep 2014]

LSM has also been integrated with age, gender, HBV DNA level into a regression formula to predict HCC with good accuracy.40 Adding LSM to another commonly used HCC risk score REACH-B score achieved a higher accuracy to predict liver-related events (of which 60% were HCC) when compared to REACH-B score alone (area under the receiver-operating characteristics curve 0.81 vs. 0.63).41 Although serum-based non-invasive tests are probably equally popular for assessing liver fibrosis, so far no HCC risk score has been developed based on these tests.

Current recommendations and unmet need

Portal hypertension is one of the most lethal complications of chronic liver disease.42 Thus, it is vital to identify patients with varices and institute primary prophylaxis. According to the American Association for the Study of Liver Diseases, all diagnosed patients with cirrhosis should undergo screening esophagogastroduodenoscopy (EGD).43 For patients without varices during screening, surveillance EGD should be done after two to three years. For those with small varices, surveillance EGD is recommended after one to two years. Annual EGD is warranted in patients with liver decompensation.43

However, EGD is unpleasant. Some patients at risk would never agree to undergo EGD because of the perceived discomfort. On the other hand, many other patients go through the procedure with negative findings. This may cause unnecessary suffering and increase health costs. The use of thrombocytopenia and splenomegaly has been proposed to identify patients with portal hypertension and varices, but the accuracy remains limited.44

Non-invasive tests and portal hypertension

Ascites, hepatic encepalopathy, and variceal bleeding are some of the complications of liver cirrhosis. The development of these events is due to portal hypertension. The gold standard for detecting portal hypertension is through the measurement of hepatic venous pressure gradient (HVPG). However, it is invasive and not readily available. Therefore, a number of studies have evaluated the use of non-invasive tests to predict portal hypertension (Table 2). One of the most commonly used is transient elastography. Given that fibrosis is a major contributor to elevated hepatic resistance (measured by HVPG), the role of transient elastography as a surrogate measure of HVPG has been studied.45 Several cutoff levels have been proposed ranging from 8.7 kPa (HVPG >6 mmHg) to 34.9 kPa (HVPG >10 mmHg) depending on the population being tested.4647 It has a sensitivity of 63-100% and a specificity of 41-96% to determine portal hypertension.4647484950 In addition, in a study among cirrhotics, an LSM of >21.1 kPa is as accurate as HVPG in identifying patients at risk portal hypertensive complications.48

Table 2.

The application of non-invasive tests of fibrosis in diagnosing portal hypertension

Splenomegaly and hypersplenism are features of portal hypertension. Indeed, spleen stiffness (54 kPa) can predict survival free complications among HCV-related cirrhotic patients.4851 However, it should be highlighted that transient elastography measures a core of tissue that is 4 cm in length; it has not been optimized for the measurement of spleen stiffness. In that regard, other physical measurements such as acoustic radiation force impulse may be more appropriate.52

Furthermore, the use of duplex doppler ultrasonography has been an attractive non-invasive test to determine portal hypertension by assessing the vascular anatomy and its hemodynamics. Parameters such as portal blood flow and velocity, resistive and pulsatility indices have also been explored to predict HVPG although with conflicting results. In a study of cirrhotic patients with different etiologies, portal vein velocity was found to correlate with HVPG, but the findings have not been confirmed by all studies.535455 Other examinations of the hepatic, splenic, superior mesenteric arteries were not proven to be correlated with HVPG.535455565758 Interestingly, some ultrasound parameters such as hepatic waveforms and damping index may be used to determine the response to medications to decrease portal pressure.5960 In contrast, portal vein velocity is not useful for the monitoring of response to terlipressin.5458 These conflicting results may be due to differences in techniques used and heterogeneity of populations being studied such as of etiology of cirrhosis, Child Pugh score, and use of medications.

A Korean group further developed a simple risk score comprising bilirubin and platelets to predict HVPG.61 It has a sensitivity of up to 88% and specificity of up to 86% in predicting HVPG >10 mmHg. Other tests like the Lok index and FIB-4 had fair accuracy in predicting HVPG.4961

Non-invasive tests and varices

As mentioned above, EGD should be performed for varices screening in cirrhotic patients, but the procedure is unpleasant and often omitted. Since non-invasive tests of fibrosis can reflect portal hypertension, it is logical to consider their application in selecting patients for EGD. LSM has the highest accuracy with a sensitivity of 76-91% and specificity varies of 28-88% to detect esophageal varices (Table 3).50516263 Some authors used acoustic radiation force impulse of spleen and liver with good accuracy (ARFI spleen sensitivity 90% and specificity 76%; ARFI liver sensitivity 83% and specificity 76%).6364 Several studies have evaluated the platelet-to-spleen ratio with an adequate sensitivity of 64-100% and specificity 64-93%.44516566 Furthermore, to predict high risk varices or variceal bleeding, ARFI and Child-Pugh class were noted to correlate with these end points.6467 Other blood tests that were determined to predict varices were platelet count (sensitivity 56-76%; specificity 64-88%) and AST-to-platelet Index (sensitivity 59-86%; specificity 64-81%).6264686970 Among the doppler ultrasound parameters only hepatic artery resistive index was found to be associated with presence of varices.5557

Table 3.

Non-invasive tests of fibrosis and varices

In the recent Baveno VI guideline, some of these non-invasive tests were already incorporated to stratify patients.71 It recommends that patients with LSM <20 kPa and platelet count >150,000 have very low risk of having large varices; screening EGD can be avoided. However, these very low risk patients should undergo annual transient elastography and platelet count.