Annals of Internal Medicine: Encephalopathy Topic Collection

Variations in the Promoter Region of the Glutaminase Gene and the Development of Hepatic Encephalopathy in Patients With Cirrhosis A Cohort Study

Romero-Gómez M, Jover M, Del Campo JA, et al. — Tue, 07 Sep 2010 00:00:00 GMT

Background:

Hepatic encephalopathy is a major complication of cirrhosis and is associated with a poor prognosis.

Objective:

To identify mutations in the gene sequence for glutaminase in humans that could be responsible for the development of hepatic encephalopathy in patients with cirrhosis.

Design:

Cohort study.

Setting:

Outpatient clinics in 6 Spanish hospitals.

Patients:

109 consecutive patients with cirrhosis in the estimation cohort, 177 patients in the validation cohort, and 107 healthy control participants.

Measurements:

Patients were followed every 3 or 6 months until the development of hepatic encephalopathy or liver transplantation, death, or the end of the study.

Results:

The genetic analyses showed that glutaminase TACC and CACC haplotypes were linked to the risk for overt hepatic encephalopathy. Mutation scanning of the glutaminase gene identified a section in the promoter region where base pairs were repeated (a microsatellite). Over a mean follow-up of 29.6 months, hepatic encephalopathy occurred in 28 patients (25.7%) in the estimation cohort. Multivariable Cox models were used to determine the following independent predictors: Childâ€“Turcotteâ€“Pugh stage (hazard ratio [HR], 1.6 [95% CI, 1.29 to 1.98]; PÂ = 0.001), minimal hepatic encephalopathy (HR, 3.17 [CI, 1.42 to 7.09]; PÂ = 0.006), and having 2 long alleles of the microsatellite (HR, 3.12 [CI, 1.39 to 7.02]; PÂ = 0.006). The association between 2 long alleles of the microsatellite and overt hepatic encephalopathy was confirmed in a validation cohort (HR, 2.1 [CI, 1.17 to 3.79]; PÂ = 0.012). Functional studies showed higher luciferase activity in cells transfected with the long form of the microsatellite, which suggests that the long microsatellite enhances glutaminase transcriptional activity.

Limitation:

Other genes and allelic variants might be involved in the clinical expression of hepatic encephalopathy.

Conclusion:

This study identifies a genetic factor that is associated with development of hepatic encephalopathy in patients with cirrhosis.

Primary Funding Source:

Instituto de Salud Carlos III, Spanish Ministry of Health.

Hepatic Encephalopathy in Our Genes?

Albrecht J. — Tue, 07 Sep 2010 00:00:00 GMT

Hepatic encephalopathy is a complex disorder characterized by gradual impairment of the ability to perform mental tasks and to react to external stimuli. It can eventually evolve to coma. Hepatic encephalopathy results from inefficient clearance of toxins, mainly ammonia, from the blood (1). Cirrhosis is the major cause of chronic liver dysfunction and affects 1 million Europeans (2) and 5.5 million Americans (3). In Europe, cirrhosis accounts for 13.7 per 100 000 deaths—only slightly below the rate for pneumonia (15.5 per 100 000 deaths) but higher than that for diabetes (13.4 per 100 000 deaths) or car accidents (9.1 per 100 000 deaths) (2).

Rifaximin maintained remission from hepatic encephalopathy longer than placebo in patients with cirrhosis

Story BT, Kowdley KV. — Tue, 17 Aug 2010 00:00:00 GMT

Question

In patients who are in remission from hepatic encephalopathy associated with cirrhosis, does rifaximin delay recurrence longer than placebo?

Methods

Design

Randomized placebo-controlled trial. ClinicalTrials.gov NCT00298038.

Allocation

{Concealed}*.†

Blinding

Blinded (patients, clinicians, data collectors, outcome assessors, {investigators, and statisticians}*).†

Follow-up period

6 months.

Setting

70 centers in the USA, Canada, and Russia.

Patients

299 patients ≥ 18 years of age (mean age 56 y, 61% men) who had ≥ 2 unprovoked episodes of overt hepatic encephalopathy (Conn score ≥ 2; range of scores 0 to 4 [worst]) associated with cirrhosis in the past 6 months but were in remission at enrolment (Conn score 0 or 1), and had scores ≤ 25 on the Model for End-Stage Liver Disease (MELD) scale (range of scores 6 to 40 [worst]). Exclusion criteria included expected liver transplantation within 1 month, conditions known to precipitate hepatic encephalopathy, chronic renal insufficiency, respiratory insufficiency, anemia, and electrolyte abnormality.

Intervention

Rifaximin, 550 mg twice daily (n = 140), or matching placebo (n = 159) for 6 months.

Outcomes

Time to first breakthrough episode of hepatic encephalopathy (Conn score ≥ 2 or an increase in Conn score from 0 to 1 plus a 1-unit increase in asterixis grade), time to first hospitalization involving hepatic encephalopathy (as reason for or occurring during hospitalization), and adverse events.

Patient follow-up

{99%}* (intention-to-treat analysis).

Main results

Rifaximin increased time to first breakthrough episode of hepatic encephalopathy and time to first hospitalization involving hepatic encephalopathy (Table). Groups did not differ for adverse events (80% in each group).

Conclusion

In patients who were in remission from hepatic encephalopathy associated with hepatic cirrhosis, rifaximin maintained remission longer than placebo.Rifaximin vs placebo to prevent recurrence of hepatic encephalopathy (HE)‡OutcomesRifaximinPlaceboAt 6 moRRR (95% CI)NNT (CI)Breakthrough episode of HE22%46%50% (29 to 66)5 (4 to 8)Hospitalization involving HE14%23%47% (12 to 68)10 (7 to 39)‡Abbreviations defined in Glossary. RRR, NNT, and CI calculated from hazard ratios and control event rates in article.