Non-invasive Evaluation of Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease by Assessment of Spleen Stiffness Using VCTE by FibroScan.

A new term, compensated advanced chronic liver disease (cACLD) defining patients in the early phases of severe chronic liver disease, including both patients with severe fibrosis or pre-cirrhotic patients and patients with compensated cirrhosis is considered very helpful for both clinical practice and research purposes. Cirrhosis should no longer be regarded as a terminal disease and the concept of a dynamic process is increasingly accepted.

Currently, the management of patients with cACLD includes assessment for severity of portal hypertension and risk stratification. Cirrhosis is currently classified into two main prognostic stages: compensated and decompensated cirrhosis. This classification depends on the presence or absence of clinically evident decompensating events (specifically ascites, variceal hemorrhage, and encephalopathy). The Child-Turcotte-Pugh (CTP) classification has been used to stratify patients with cirrhosis. Patients with cirrhosis belonging to the CTP-A class are compensated, whereas those in the CTP-B/C class are mostly decompensated. Similarly, Model for End-Stage Liver Disease (MELD) is a reliable measure of mortality risk in patients with end-stage liver disease and used to help prioritize organ allocation for transplant. However, MELD scores of <10, typically seen in CTP-A, are unlikely to have prognostic value as the likelihood of clinical events in a 1 to 2-year time frame is low. Therefore, both CTP and MELD scores best stratify cirrhosis patients with decompensation and have limited use in compensated cirrhotics who have no liver-related symptoms.

Patients with compensated cirrhosis are sub-staged based on the severity of portal hypertension. However, measurement of portal pressure through direct puncture of the portal vein is risky and not routinely performed. Therefore, portal pressure is assessed indirectly by calculation of hepatic vein pressure gradient (HVPG) by measuring the difference between wedge and free hepatic venous pressure.The normal value of HVPG is between 3 and 5 mmHg. Currently, the severity of portal hypertension is defined as mild when HVPG is 6 but <10 mm Hg, ≥10 mm Hg as clinically significant portal hypertension (CSPH), and ≥12 mm Hg as severe portal hypertension (SPH). Evaluation of a compensated cirrhotic by HVPG is ideal for risk stratification as CSPH is associated with an increased risk of varices, decompensation (ascites, variceal hemorrhage and/or hepatic encephalopathy) and hepatocellular cancer. However, measurement of HVPG is cumbersome, invasive, non-standardized and often limited to tertiary care centers due to limited expertise. Therefore, there is a need for non-invasive tools that can estimate HVPG easily, reproducibility and with high diagnostic accuracy.

Liver stiffness measurement (LSM) by vibration controlled transient elastography (VCTE) is currently used for non-invasive diagnosis liver fibrosis in patients with NAFLD (non alcoholic fatty liver) and NASH (non alcoholic steatohepatitis). In patients with cirrhosis, LSM is likely indicative of cumulative stiffness from underlying liver fibrosis and portal hypertension. Portal hypertension-related splenomegaly is frequently accompanied by patients with cirrhosis due to portal venous congestion and hyperplasia of splenic tissue, and its usefulness for diagnosis of portal hypertension has been studied. However, the direct relationship between the size of the spleen and the severity of portal hypertension is still under debate. Recent studies have focused on ultrasound-based measurement of spleen stiffness (SS) as it is reflective of portal hypertension-related changes in the spleen, including splenomegaly. Measurement of SS has also accurately predicted both the presence of varices and the degree of portal hypertension. Spleen Stiffness (SS) by VCTE is an emerging tool for assessment of portal hypertension and its feasibility has been reported both in adults and children.

FibroScan is a diagnostic device based on VCTE. It measures a mean tissue stiffness (between 25 mm and 65 mm in the liver of non-obese patients) in a medium considered as homogeneous and isotropic. FibroScan is equipped with a probe composed of an ultrasonic transducer (3.5 MHz for non-obese patients) mounted on the axis of a vibrator. This vibrator generates a low-frequency pulse (50 Hz and 2 mm peak-to-peak amplitude for LS measurement in non-obese patients) that induces a shear wave that propagates through the tissue. Shear wave propagation is followed by pulse-echo ultrasound and the strains induced in the tissue are computed as a function of time and depth. Tissue stiffness E is deduced from the shear wave speed (SWS or Vs) obtained by measuring the slope of the shear wave on the strain matrix using a time-of-flight algorithm (E = 3ρVs² where ρ is the body mass of the tissue). In soft tissues, the body mass is close to the one of water. A body mass ρ of 1,000 kg/m3 was used for the density of the spleen. The ultrasound acquisition is performed between 20 mm and 80 mm below skin surface and the measurement is performed between 25 mm and 55 mm. The stiffness of the spleen ranges between 5 kPa and 100 kPa. It is currently undergoing regulatory approval as a diagnostic tool for non-invasive assessment of portal hypertension.

The natural history of NASH or other chronic liver disorders with advanced fibrosis/ cirrhosis across the different clinical stages of cirrhosis is currently not well understood. Therefore, non-invasive tools that can assess the severity of cirrhosis and risk stratify prior to decompensation is currently an unmet need. Simultaneous assessment of LSM and SS using VCTE may eventually allow for a noninvasive, immediate, objective and efficient method for estimation of disease severity in patients with NASH cirrhosis. Moreover, assessment over time of LSM and SS may also allow for assessment of disease progression or regression from treatment interventions. It is anticipated that baseline measurements of SS/LSM and longitudinal changes (ΔSS/Δt or ΔLSM/Δt) will serve as a prognostic tool in patients with cACLD.