Clinical trial NCT05044663: Liver and Splenic Stiffness in Predicting Esophageal Varices Needing Treatment in NASH Related Compensated Advanced Chronic Liver Disease.
Official title: Liver and Splenic Stiffness in Predicting Esophageal Varices Needing Treatment in NASH Related Compensated Advanced Chronic Liver Disease - A Cross-Sectional Study.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Chronic Liver Disease
Lead sponsor: Institute of Liver and Biliary Sciences, India
Sponsor class: OTHER
First posted: 2021-09-16
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
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.

Brief 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.

Eligibility criteria: Inclusion Criteria:

* NASH will be diagnosed by liver biopsy or ultrasound steatosis / Fibroscan CAP \> 250 dB + any 1 criteria of metabolic syndrome:

  1. Waist circumference 90 ≥ cm for males or ≥80 cm for females
  2. Triglycerides ≥150 mg/dL
  3. HDL-C \< 40 mg/dL in males or \< 50 mg/dl in females
  4. systolic blood pressure (SBP) ≥130 mm Hg or diastolic blood pressure (DBP) ≥ 85 mmHg or both and
  5. Fasting plasma glucose ≥ 100 mg/dL. cACLD is defined with Liver stiffness ≥10 kPa. Ultrasound examination, blood examination and upper gastrointestinal endoscopy will be performed within 1 month of Fibroscan examination. HVPG if indicated will be done within 1 month of Fibroscan. Patients of viral hepatitis (HBV / HCV) related cACLD will be taken as control.

Exclusion Criteria:

1. Age \< 18 and \> 70 years,
2. BMI \> 35, past or present history of decompensation (ascites, variceal bleed, hepatic encephalopathy, jaundice),
3. Child Pugh B or C,
4. unreliable liver and splenic stiffness in Fibroscan examination,
5. Transjugular intrahepatic portosystemic shunt, significant alcohol intake (\> 20gm/day in last year),
6. Acute on chronic liver failure,
7. AST/ALT \> 100 IU/l,
8. Hepatocellular carcinoma or any space-occupying lesion in the liver,
9. Portal vein thrombosis,
10. Biliary obstruction,
11. HVOTO,
12. Cardiac failure,
13. Prior variceal endotherapy or ongoing beta blocker treatment for varices,
14. HIV,
15. Any malignancy,
16. Pregnancy,
17. ICD / pacemaker,
18. No consent.

Primary outcomes:
measure: 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.
timeFrame: Day 0
Secondary outcomes:
measure: Correlation of the liver and splenic stiffness with HVPG in patients of NASH related cACLD will be assessed.
timeFrame: Day 0
measure: Utility of various noninvasive tests will be assessed in predicting presence of esophageal varices needing treatment in patients of HBV or HCV related cACLD
timeFrame: Day 0
Other outcomes:
Locations:
city: New delhi
country: India
facility: Institute of Liver & Biliary Sciences
state: Delhi
Study officials:
References: