Non-invasive Evaluation of Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease by Assessment of Spleen Stiffness Using Vibration Controlled Transient Elastography
Non-invasive Evaluation of Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease by Assessment of Spleen Stiffness Using Vibration Controlled Transient Elastography
Hypothesis: The severity of portal hypertension in compensated advanced chronic liver disease
 (cACLD) can be assessed using vibration controlled transient elastography (VCTE) via the
 FibroScan® 502 Touch by measuring SS (splenic stiffness) Specific Aims: SS by VCTE will be
 measured in this single center clinical study comprising of 200 patients with cACLD (deﬁned
 by LSM ≥10 kilopascals (kPa) according to the Baveno VI recommendations) who have not had a
 liver transplant and 100 subjects who are post-liver transplant. The association between
 baseline SS values will be examined in relation to the manifestations of portal hypertension
 such as esophageal or gastric varices.

 Specific Aim: To examine the relationship between SS and the presence of esophageal and
 gastric varices in patients with compensated advanced chronic liver disease (cACLD).

 Proposed Study Design: This is a cross sectional study that evaluates the relationship
 between SS by VCTE in patients with cACLD and manifestations of portal hypertension.
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.
Inclusion Criteria:

 1. Adults aged 18 years or older

 2. Ability to provide informed consent

 3. Previous Fibroscan with LSM ≥10 kilopascals (kPa)

 Exclusion Criteria:

 1. Inability or refusal to provide informed consent

 2. Fasting for less than three hours prior to the scan

 3. Subject is a pregnant or lactating female

 4. Subject with current, significant alcohol consumption

 5. Subject is unable to reliably quantify alcohol consumption based upon local study
 physician judgment

 6. Patients with a pacemaker or defibrillator

 7. Acute hepatitis defined as AST/ALT > 500 U/L