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Development and Validation of a Clinical-Genetic Risk Score to Predict Hepatic Encephalopathy in Patients With Liver
Antonio Gil-Gómez1,2, Javier Ampuero1,2,3, Ángela Rojas1,2
1SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain.
Insights
Genetic factors significantly impact hepatic encephalopathy (HE) risk in liver cirrhosis patients. A new clinical-genetic score, combining genetic markers with clinical data, accurately predicts HE incidence and severity.
Area of Science:
- Genetics and Genomics
- Hepatology
- Clinical Medicine
Background:
- Hepatic encephalopathy (HE) is a serious complication of liver cirrhosis.
- The influence of genetic background on HE development is not fully understood.
Purpose of the Study:
- To investigate the impact of genetic factors on overt HE in liver cirrhosis patients.
- To develop and validate a combined clinical-genetic risk score for predicting HE.
Main Methods:
- Genotyping of 600 liver cirrhosis patients for 60 single nucleotide polymorphisms and a GLS microsatellite.
- Development of a genetic score and a comprehensive clinical-genetic risk score.
- Longitudinal follow-up for at least 5 years to assess HE incidence and severity.
Main Results:
- Specific single nucleotide polymorphisms (rs601338, rs5743836, rs2562582, rs313853) and the GLS microsatellite independently predicted HE.
- The clinical-genetic HE Risk score, incorporating bilirubin, albumin, genetic score, and prior HE episodes, showed strong predictive power (C-index 0.83 internal, 0.74 external).
- Patients stratified into low-risk and high-risk groups demonstrated significantly different HE probabilities over 5 years.
Conclusions:
- Genetic background plays a crucial role in the risk and severity of overt HE in liver cirrhosis.
- The developed clinical-genetic HE Risk score is a valuable tool for predicting overt HE in patients with cirrhosis.
Introduction:
We aimed to define the impact of the genetic background on overt hepatic encephalopathy (HE) in patients with liver cirrhosis by developing a combined clinical-genetic risk score.
Methods:
Patients suffering from liver cirrhosis from the outpatient clinics of 4 hospitals (n = 600) were included and followed up for at least 5 years until HE bouts, liver transplant, or death. Patients were genotyped for 60 candidate single nucleotide polymorphisms together with the microsatellite in the promoter region of the gene GLS.
Results:
Single nucleotide polymorphisms rs601338 (FUT2), rs5743836 (TRL9), rs2562582 (SLC1A3), rs313853 (SLC1A5), and GLS microsatellite did predict independently the incidence and severity of overt HE and were included as genetic score. Competing risk analysis revealed that bilirubin (subhazard ratio [sHR] 1.30 [1.15-1.48], P < 0.001), albumin (sHR 0.90 [0.86-0.93], P < 0.001), genetic score (sHR 1.90 [1.57-2.30], P < 0.001), and previous episodes of overt HE (sHR 2.60 [1.57-4.29], P < 0.001) were independently associated to HE bouts during the follow-up with an internal (C-index 0.83) and external validation (C-index 0.74). Patients in the low-risk group had 5% and 12% risk of HE at 1 (log-rank 92.1; P < 0.001) and 5 (log-rank 124.1; P < 0.001) years, respectively, whereas 36% and 48% in the high-risk group.
Discussion:
The genetic background influenced overt HE risk and severity. The clinical-genetic HE Risk score, which combined genetic background together with albumin, bilirubin, and previous episodes of overt HE, could be a useful tool to predict overt HE in patients with cirrhosis.
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