ENDOSCOPIC ULTRASOUND LIVER PALPATION AS A SCREENING TOOL FOR ADVANCED FIBROSIS AND CIRRHOSIS

Background: Hepatic encephalopathy (HE) is associated with increased mortality, falls, and frequent hospitalizations. Patient reported outcomes (PROs) are useful tools to assess health-related quality of life (HRQOL) measures such as impairment of sleep, cognition, or activity. PROs have also been shown to be reliable & valid tools to detect early signs of HE. Many clinicians initiate lactulose when patients present with poor PROs without cognitive testing, however data are limited regarding the efficacy of this strategy.
Methods: The Mi-Kristal trial is a single-center, randomized study to determine whether a 28-day regimen of Kristalose^®, a crystalline lactulose therapy (20g BID) improves HRQOL in people with poor PROs. We enrolled patients with cirrhosis, portal hypertension, no prior HE, & Activity Impairment attributed to cirrhosis >3 (scale 0-10) because this score was highly predictive of overt HE in prior studies. Endpoints included the short form-8 (SF-8), animal naming test (ANT), falls, and a 4-point Likert scale rating sleep quality (very bad to very good).
Results: Fifty-six subjects were randomized, 52 subjects completed the protocol; 25 Kristalose and 27 no treatment. Median Baseline MELD-Na was 11 and ANT was 19 without differences between the groups at baseline. At Day 28 no significant difference was observed using the SF-8: subjects on Kristalose had an 8.1 point increase (95%CI 3.7-12.4) compared to 6.6 (95%CI 2.3-10.8) in control (p=0.6). Significant improvements were observed in subjects on Kristalose using the ANT which increased by 3.7 (95%CI 2.1-5.4) vs control - -0.2 (95%CI -1.7-1.4); 32% on Kristalose had a 5-point increase in ANT vs 11% of control. Falls were reported by 11% in control and 4% on Kristalose. At the end of the trial, 92% on Kristalose reported good sleep compared to 52% of control. Compared to control, Kristalose was associated with a significant 0.6 (95%CI0.3-1.0) point improvement in sleep quality and a significant 1.7 (95%CI0.3-3.1) point decrease in activity impairment.
Conclusion: Among patients with activity impairment at risk for HE, a 28-day crystalline lactulose regimen led to improved sleep, cognitive function & activity impairment. No significant difference in HRQOL was observed using the SF-8 possibly because the instrument is insensitive to change in this context or a longer treatment duration is required. A 6-month trial is planned. Our findings support the use of PROs to assess for benefit of HE-therapy and that early treatment improves select PROs.

Background
Endoscopic “palpation” of the liver is possible via endoscopic ultrasound (EUS). Regardless of body habitus, the EUS probe can be reproducibly positioned close to the liver surface. With a standard turn of the big wheel, the EUS probe indents the liver surface, and the level of indentation can be measured with sonographic calipers. Our hypothesis is that a fibrotic liver is harder to indent and the degree of indentation correlates with liver fibrosis severity. We aim to correlate EUS liver palpation with histology in patients with NAFLD and compare its predictive value for fibrosis staging to more conventional screening methods.
Methods
This was a cross sectional study of prospectively collected data. Consecutive patients at 3 hospitals between June 2021 and Nov 2022 underwent EUS liver palpation with subsequent liver biopsy. Index scores of Fibrosis-4 Index (FIB-4), AST to Platelet Ratio Index (APRI), NAFLD Fibrosis Score (NFS), and Agile 3+/4 per transient elastography (TE, i.e. Fibroscan) were calculated. Comparisons between EUS liver palpation and index scores/TE were performed using area under the curve (AUC) analysis.
Results
61 patients were evaluated. The mean age was 50. 64.5% were female. Average BMI was 41.2. EUS liver palpation significantly correlated with fibrosis stage on liver biopsy (p=0.0002) with lower indentation values at higher fibrosis stages [Figure 1A]. EUS palpation had AUC of 0.73, 0.80, and 0.98 for discriminating significant fibrosis (F0-1 vs F2-4), advanced fibrosis (F0-2 vs F3-4), and cirrhosis (F0-3 vs F4) respectively [Figure 1B]. EUS liver palpation was superior to APRI and NFS in predicting cirrhosis (p=0.004 and 0.038 respectively).. Indentation of ≤3.5mm yields sensitivity, specificity, positive predictive value, and negative predictive value of 64.7%, 100%, 100%, and 88% respectively for detecting advanced fibrosis.
35/61 (57%) patients had TE performed. In this sub-cohort, EUS palpation had higher AUC values than TE and Agile 3+/4 but this was not significantly different [Figure 2A]. Combination of palpation + Agile 3+/4 for advanced fibrosis and cirrhosis cutoffs were superior to TE alone (p=0.0018 and 0.017 respectively). Lastly, we discovered body mass index (BMI) may be a confounder for TE (Pearson coefficient r=0.70, p=0.0005) but not for EUS liver indentation (r=-0.30, p=0.062) [Figure 2B].
Conclusions
EUS liver palpation is a reliable, novel, and easy-to-use tool to screen for advanced fibrosis in patients with NAFLD, and may be superior to APRI and NFS in predicting cirrhosis. This can be useful in patients with obesity in which an elevated BMI may confound TE results, and may be a valuable minimally invasive tool for endohepatologists in liver fibrosis screening for the NAFLD population. Larger multicenter studies will help to better define the utility and reproducibility of EUS liver palpation.