A genetic variant in the promoter of phosphate‐activated glutaminase is associated with hepatic encephalopathy

Mayer, L. B.; Krawczyk, Marcin; Grünhage, F; Lammert, Frank; Stokes, Caroline S.

doi:10.1111/joim.12374

Cited by 7 publications

(7 citation statements)

References 49 publications

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“…Gene selection, location, and ID of each single nucleotide polymorphism tested are detailed in The microsatellite in GLS was assessed as previously described (17). According to the distribution of the number of repeats, and in agreement with previous studies (17,24), the length of the microsatellite was set a cutoff of 14 repeats for short or long alleles (Figure S2, Supplementary Digital Content 1, http://links.lww.com/AJG/B928).…”

Section: Genes and Polymorphisms Assayedmentioning

confidence: 98%

Development and Validation of a Clinical-Genetic Risk Score to Predict Hepatic Encephalopathy in Patients With Liver Cirrhosis

et al. 2021

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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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Section: Genes and Polymorphisms Assayedmentioning

confidence: 98%

Development and Validation of a Clinical-Genetic Risk Score to Predict Hepatic Encephalopathy in Patients With Liver Cirrhosis

et al. 2021

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“…Notably, the presence of baseline portosystemic shunts was seen by the immediately previous ultrasound, instead of other methods with more sensitivity. Finally, we did not evaluate some genetic determinants that could influence the results of the OGC, such as the microsatellite in the promoter region of the glutaminase gene …”

Section: Discussionmentioning

confidence: 99%

“…Finally, we did not evaluate some genetic determinants that could influence the results of the OGC, such as the microsatellite in the promoter region of the glutaminase gene. 31,32 The OGC is an easy and reliable tool that could reflect a poorer condition of the liver function. Analyzing both baseline and postload ammonia concentration, the OGC could help to identify at-risk patients and guide the counselling (notably, driving and nutrition) and primary prevention for HE.…”

Section: Discussionmentioning

confidence: 99%

Oral glutamine challenge is a marker of altered ammonia metabolism and predicts the risk of hepatic encephalopathy

Ampuero

Gil

Viloria

et al. 2019

Liver International

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Background The current therapies for hepatic encephalopathy (HE) are not completely effective in all patients, probably due to the physiopathological heterogeneity and the different conditions underlying the bout of HE. We hypothesized that oral glutamine challenge (OGC) is able to predict the risk of HE through the identification of various features and types of HE. Methods We included 238 cirrhotic patients (198 without and 40 with a previous HE episode) that underwent OGC, obtaining baseline and 60 minutes post‐load ammonia levels. Combined evaluation of baseline hyperammonemia (>78 mcg/dL) and impaired OGC (Δ >32 mcg/dL) defined low‐, intermediate‐ and high‐risk groups. Patients were censored at HE, liver transplantation and death or 6 years of follow‐up. Results The 28.3% (56/198) of the main cohort suffered from HE during the follow‐up. In the competing risk analysis, both intermediate‐ (subhazard ratio (sHR) 2.01 (95% CI 1.00‐4.14); P = .048) and high‐risk groups (sHR 4.67 (95% CI 2.19‐9.98); P = .0001) were associated with the first HE episode, together with age and albumin. Similar results were found for repeated HE events. The cumulative incidence for HE of the high‐risk group was two and four times greater than the intermediate‐ and low‐risk groups, respectively. The HE grade was also higher in individuals with the greatest risk (P = .035). The most common precipitant factor was diuretics in the high‐risk group, while infections and electrolyte imbalance predominated in the rest of patients. Conclusion Oral glutamine challenge identified patients at risk of HE and defined specific features of the episodes. This tool could be useful in the decision‐making process for the adequate management of HE.

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“…1 In previous studies, microsatellites of the promoter region in the human glutaminase gene encoding for higher enzyme activity have been associated with the development of HE in humans cirrhosis; therefore, it is not surprising that this genetic variant might predispose for ACLF. 23,24 Besides genetics, epigenetics might also play an important role in patients developing the syndrome. Unfortunately, this is poorly investigated, but there are some hints in animal models that suggest epigenetics is important in the development of liver fibrosis and also liver injury.…”

Section: Genetics and Epigeneticsmentioning

confidence: 99%

Predisposing Factors in Acute-on-Chronic Liver Failure

Trebicka

2016

Semin Liver Dis

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Acute-on-chronic liver failure (ACLF) is a syndrome with high short-term mortality in patients with chronic liver disease. The definition of ACLF has been addressed recently in many publications, and despite regional differences the number and severity of organ failures are decisive for the presence and severity of ACLF. However, the predisposition of patients to develop ACLF has not been addressed in prospective studies. Several predisposing factors for ACLF have been mentioned, but still clear-cut analysis and the sequential processes have not been explored. One reason is that different factors might predispose in one setting and might be the precipitating event in another, thus rendering the generalization of predisposing factors difficult. However, genetic factors, lifestyle, past medical history, aging, latent chronic infections, and the severity of the liver disease and portal hypertension might predispose for the development of ACLF after proper injury and response.

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A genetic variant in the promoter of phosphate‐activated glutaminase is associated with hepatic encephalopathy

Abstract: Abstract. Mayer LB, Krawczyk M, Gr€ unhage F,

Cited by 7 publications

References 49 publications

Development and Validation of a Clinical-Genetic Risk Score to Predict Hepatic Encephalopathy in Patients With Liver Cirrhosis

Development and Validation of a Clinical-Genetic Risk Score to Predict Hepatic Encephalopathy in Patients With Liver Cirrhosis

Oral glutamine challenge is a marker of altered ammonia metabolism and predicts the risk of hepatic encephalopathy

Predisposing Factors in Acute-on-Chronic Liver Failure

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