Ammonia-to-Urea Ratio: A Noninvasive First-Line Tool for Detecting Clinically Significant Portal Hypertension

Abstract

Introduction: Cirrhosis progresses from compensated to decompensated phases, often marked by portal hypertension and complications like ascites, variceal hemorrhage, and hepatic encephalopathy. The ammonia-to-urea (A-to-U) ratio, reflecting urea cycle efficiency, may offer superior diagnostic performance compared to plasma ammonia levels alone. This study compared the diagnostic accuracy of the A-to-U ratio and plasma ammonia levels for identifying portal hypertension.

Methods: We conducted a derivation (2019-2020) and validation (2020-2022) study in patients with chronic liver disease. In the derivation study, outcomes included imaging findings of portal hypertension and clinically significant portal hypertension (CSPH) per BAVENO VII criteria. Validation outcomes encompassed CSPH, gastroesophageal varices, and portal hypertensive gastropathy.

Results: In the derivation study (n = 180), the A-to-U ratio, but not plasma ammonia, showed high diagnostic accuracy for detecting imaging findings suggestive of portal hypertension and CSPH (A-to-U ratio > 1.53 mg/g; diagnostic odds ratio [dOR], 4.04 [95% CI, 1.98-8.24; p < 0.0001] and dOR, 5.71 [95% CI, 2.87-11.37; p < 0.0001], respectively), and this association with CSPH remained significant after adjustment for renal function. In the validation study (n = 232), an A-to-U ratio > 1.53 mg/g had a dOR of 9.42 (95% CI, 4.63-19.21; p < 0.0001) for the diagnosis of CSPH. An A-to-U ratio > 1.53 mg/g showed independent associations with esophageal varices (dOR 4.44; 95% CI, 1.44-13.72; p = 0.01) and portal hypertensive gastropathy (dOR 9.33; 95% CI 2.65-32.92; p = 0.0005), whereas the BAVENO VII criteria did not.

Discussion: Our study suggests that an A-to-U ratio > 1.53 mg/g may serve as a useful noninvasive tool for identifying CSPH, gastroesophageal varices, and portal hypertensive gastropathy in patients with chronic liver disease.

Keywords: ammonia‐to‐urea ratio; cirrhosis; clinically significant portal hypertension; gastroesophageal varices; portal hypertension; portal hypertensive gastropathy.

FIGURE 1

Distribution of the ammonia‐to‐urea ratio according to BAVENO VII strata based on the rule of 5 (10–15–20–25 kPa) for stratifying progressively increasing risk related to clinically significant portal hypertension (CSPH). Panel (A) reports the results of the derivation study, and panel (B) reports the results of the validation study. The distribution of the ammonia‐to‐urea ratio is illustrated using violin plots and integrated box plots. The dashed horizontal line corresponds to the 1.53 mg/g threshold for the ammonia‐to‐urea ratio. LSM, Liver stiffness measurement; * p < 0.05 for pairwise comparison using the Conover post hoc test.