Pharmacological decrease of liver stiffness is pressure-related and predicts long-term clinical outcome

Abstract

Liver stiffness (LS) as measured by transient elastography is increasingly used to noninvasively assess liver fibrosis. However, LS is efficiently modulated by confounders like arterial and portal pressure (PP). We here study the effect of acute hemodynamic changes on LS (measured by µFibroscan) in a rodent model of cirrhosis in response to pharmacological modulation of PP by losartan, nitric oxide donors, and propranolol. Additionally, changes of LS and the hepatic venous pressure gradient (HVPG) under propranolol therapy were assessed with regard to clinical outcomes in a human cohort of n = 38 cirrhotic patients. In the animal model, cirrhosis induction resulted in a significant increase of LS and PP. After losartan or NO application, a LS decrease of 25% was strongly correlated with a concomitant decrease of mean arterial pressure (MAP) and PP. In contrast, acute propranolol administration decreased heart rate but not MAP resulting in stable LS. In the human cohort, most patients ( n = 25, 66%) showed a LS decrease after propranolol treatment initiation which significantly correlated to HVPG ( r = 0.518, P < 0.01) but was not accompanied by statistically significant changes in transaminases or model of end-stage liver disease (MELD). On multivariate analysis, patients with decreasing LS on propranolol had a decreased risk for experiencing a transplantation or death than patients with increasing LS irrespective of HVPG. In conclusion, LS changes after pharmacological interventions are influenced by hemodynamic effects on arterial and portal pressure. In humans, a LS decrease may be predictive of improved outcome irrespective of MELD scores and may serve as an additional follow-up tool in the future. NEW & NOTEWORTHY Liver stiffness (LS) is efficiently modulated by changes in portal venous and systemic pressures in an animal model of liver cirrhosis irrespective of baseline LS and portal pressure values. In humans, most patients show a decrease in LS after propranolol treatment initiation without statistically significant changes in transaminases or model of end-stage liver disease (MELD) scores. A decrease in LS may be associated with improved outcome and thus another valuable tool in the follow-up of patients after propranolol treatment initiation.

A review of the use of transient elastography in the assessment of fibrosis and steatosis in the post–liver transplant patient

“…Similarly, factors that increase mean arterial pressure, such as vasopressors or aerobic exercise, increase LS measurements in both animal and human models . Changes in portal venous flow, as in the setting of pharmacologic effect on hepatic hemodynamics, transjugular intrahepatic portosystemic shunt (TIPS) placement or variceal ligation, also affect LS . For example, in a group of 14 patients undergoing TIPS placement, LS decreased by 9.2 kPa on average, whereas in a group of 11 patients undergoing esophageal ligation, LS increased by roughly 16 kPa post‐ligation …”

Noninvasive Diagnostics for Portal Hypertension: A Comprehensive Review

“…This might be explained by the fact that SSM more directly reflects portal hypertension, as it is mostly a measure of portal venous congestion, while LSM is more an estimation of liver fibrosis 49 and other factors, including arterial blood pressure. 37,105 Still, the strength of the correlation between spleen stiffness and HVPG seems to decrease with increasing severity of portal hypertension. In a recent study using 2D-SWE (SSI), 106 for instance, Spearman's ρ in patients with HVPG values > 12 mm Hg was 0.464, while a substantially stronger correlation was observed in the overall study population (Spearman's ρ ¼ 0.665).…”

“…Interestingly, there is also evidence suggesting that NSBB treatment-induced changes in LSM by VCTE hold prognostic information even beyond their relation to portal pressure; however, the underlying pathophysiological mechanisms have yet to be fully elucidated. 37…”

Hepatic Venous Pressure Gradient Response in Non-Selective Beta-Blocker Treatment—Is It Worth Measuring?

“…However, liver stiffness measured by US-based elastography methods is of limited value for assessing HVPG response due to its weak correlation with HVPG in patients with HVPG values ≥ 10 to ≥ 12 mmHg [73], i.e., patients which are considered as candidates for response-guided NSBB therapy. Of note, there is evidence suggesting that changes in liver stiffness under/following portal pressure-lowering treatments (i.e., NSBB [71] and transjugular intrahepatic portosystemic shunt [74]) hold prognostic information even beyond their relation to portal pressure; however, the underlying pathophysiological mechanisms are yet to be fully elucidated.…”

“…Spleen stiffness assessed by US-based elastography showed very promising results with a numerically (TE [75]) or even statistically significantly (point shear-wave elastography (pSWE)/virtual touch quantification (VTQ) [76]) stronger (vs. liver stiffness) correlation with HVPG. This might be explained by the fact that spleen stiffness more directly reflects portal hypertension, as it is mostly a measure of portal venous congestion, while liver stiffness is also strongly influenced by liver fibrosis [70••] and other factors, including arterial blood pressure [71,77]. However, the superiority of spleen stiffness (vs. liver stiffness) has not been confirmed by another study using both TE and twodimensional shear-wave elastography (2D-SWE)/supersonic imaging (SSI) [78].…”