Liver and Splenic Stiffness in Predicting Esophageal Varices Needing Treatment in NASH Related Compensated Advanced Chronic Liver Disease.
Condition: Chronic Liver Disease
MeSH terms: Liver Diseases; Esophageal and Gastric Varices
Study type: Observational

Summary: 
      Patients with chronic liver disease (CLD) are at risk of developing clinically significant
      portal hypertension (CSPH). In the Baveno VI consensus a new term "compensated advanced
      chronic liver disease (cACLD)'' has been proposed to better reflect that the spectrum of
      severe fibrosis and cirrhosis is a continuum in asymptomatic patients. Liver stiffness by TE
      is sufficient to suspect cACLD in asymptomatic subjects with known causes of CLD. TE values
      <10 kPa in the absence of other known clinical signs rule out cACLD; values between 10 and 15
      kPa are suggestive of cACLD but need further test for confirmation; values >15 kPa are highly
      suggestive of cACLD. Patients with a liver stiffness <20 kPa and with a platelet count
      >150,000 have a < 5 % risk of having varices requiring treatment, and can avoid screening
      endoscopy. SSM can also predict the presence of CSPH and varices requiring treatment. Some
      studies have shown superiority of splenic stiffness over liver stiffness in predicting
      varices requiring treatment likely attributable to the better performance of SSM compared
      with LSM in more severe portal hypertension because it reflects better the hemodynamic
      component of portal hypertension. However, there are few studies on NAFLD and most are on
      viral hepatitis related cACLD. Moreover, very few studies are published on splenic stiffness
      from Indian subcontinent. Similarly baseline HVPG is an important predictor of disease
      progression patients of NAFLD related cACLD, but requires invasive hepatic vein
      catheterization. Hence, we intend to do the study assessing diagnostic utility of splenic and
      liver stiffness in predicting varices needing treatment in NAFLD related cACLD and compare
      from other noninvasive markers and its correlation with HVPG.
    

Detailed description: 
      Aim - to study the diagnostic accuracy of liver stiffness and splenic stiffness in predicting
      esophageal varices needing treatment in patients of NASH related cACLD.

      Primary objective:

      To assess the utility of liver stiffness and splenic stiffness in making a composite score to
      predict presence of esophageal varices needing treatment in patients of NASH related cACLD.

      Secondary objectives:

        1. To study the correlation of liver stiffness and splenic stiffness with grade of
           esophageal varices.

        2. To study utility of other noninvasive scores, such as Baveno VI criteria, expanded
           Baveno VI criteria, LSPS (LS x spleen diameter / platelet ratio score), platelet count
           to spleen diameter ratio (PSR), AST/ALT ratio, APRI, FIB-4, in predicting presence of
           esophageal varices needing treatment in patients of NASH related cACLD.

        3. To study utility of noninvasive tests in predicting presence of esophageal varices
           needing treatment in patients of HBV or HCV related cACLD.

        4. To study correlation of liver and splenic stiffness with HVPG and MELD score in patients
           of NASH related cACLD.

           (b) Methodology:

             -  Study population: Consecutive patients of NASH related cACLD (Liver Stiffness ≥10
                kPa).

      Consecutive patients of viral hepatitis (HBV / HCV) related cACLD during the study period
      meeting the inclusion and exclusion criteria will be taken as control.

        -  Study design: An observational cross-sectional study

        -  Study period: 15 months

        -  Sample size with justification: This is a cross-sectional prevalence study. All the
           patients meeting the inclusion and exclusion criteria during the period October 2021 to
           December 2022 undergoing liver stiffness, splenic stiffness and upper gastrointestinal
           endoscopy will be included in the study.

        -  Intervention: Patients of NASH related cACLD and controls (viral hepatitis related
           cACLD) will undergo upper gastrointestinal endoscopy, liver and splenic stiffness
           measurement, ultrasound abdomen, Doppler study and routine laboratory tests. Varices
           needing treatment will be defined by Baveno VI criteria as medium or large size
           esophageal varices or the presence of high-risk stigmata findings (red wale marks,
           cherry red spots). HVPG will be done in the patients only if clinically indicated.

        -  Monitoring and assessment: Transient Elastography will be performed in morning hours
           using the FibroScan apparatus (Echosens), which consists of a 5-MHz ultrasound
           transducer probe mounted on the axis of a vibrator. The tip of the transducer (M-or XL
           probe) will be placed perpendicularly in the intercostal space, with the patient lying
           in dorsal decubitus position with the right arm in the maximal abduction. The operator
           will choose a liver portion within the right liver lobe, at least 6-cm thick and free of
           large vascular structures, and the gallbladder. Liver stiffness (LS) will be measured on
           a cylinder of hepatic tissue of 1 cm of diameter and 4 cm of length. For assessing the
           splenic stiffness (SS), the patient will be in supine position with left arm in maximum
           abduction. Ultrasonography will be used to identify and locate the spleen parenchyma, to
           choose the right place for SS measurement, and to measure the spleen diameter (long
           axis). A median value of 10 successful acquisitions, expressed in kPa, will be kept as a
           representative of the LS and SS measurements. The LS and SS measurement failure will be
           recorded when no value will be obtained after at least 10 shots. The results will be
           considered unreliable in the following circumstances: valid shots fewer than 10, success
           rate < 60%, or interquartile range / LS >30 %. Liver and splenic stiffness, LSPS score
           (LS measurement × spleen diameter / platelet count), Platelet count to spleen diameter
           ratio (PSR) will be calculated. Patient will also undergo upper gastrointestinal
           endoscopy. HVPG will be done if indicated.

        -  Statistical Analysis: Data will be entered into Microsoft Excel and will be analyzed
           using SPSS version 22. Stastical test applied will be student t test or Mann Whitney
           test to compare continuous data among patients with and without high-risk esophageal
           varices. Categorical data will be analyzed using Chi square test or Fisher Exact test
           whichever applicable. Univariate and multivariate logistic regression will be applied
           for finding the predictor of esophageal varices needing treatment. Composite score model
           will be formed using liver stiffness, splenic stiffness and radiological / laboratory
           tests to predict esophageal varices needing treatment keeping negative predictive value
           at least 0.95. Diagnostic test will be applied to find the cutoff value for liver
           stiffness and splenic stiffness by using AUROC. The correlation of liver and splenic
           stiffness with HVPG will be studied with Pearson's correlation coefficient.

        -  Adverse effects: No

        -  Stopping rule of study: No

      Expected outcome of the project:

        1. Utility of liver and splenic stiffness will be assessed to form a composite score to
           predict presence of esophageal varices needing treatment in patients of NASH related
           cACLD.

        2. Correlation of the liver and splenic stiffness with HVPG in patients of NASH related
           cACLD will be assessed.

        3. Utility of various noninvasive tests will be assessed in predicting presence of
           esophageal varices needing treatment in patients of HBV or HCV related cACLD.
    

Intervention name(s): No intervention
Intervention type(s): Other
Intervention description(s): This is an observational study
Observational model: Case-Only
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Consecutive patients of NASH related cACLD (Liver Stiffness ≥10 kPa).Consecutive patients
        of viral hepatitis (HBV / HCV) related cACLD during the study period meeting the inclusion
        and exclusion criteria will be taken as control.