Elsevier

Journal of Hepatology

Volume 63, Issue 5, November 2015, Pages 1133-1138
Journal of Hepatology

Research Article
Diabetes as a risk factor for hepatic encephalopathy in cirrhosis patients

https://doi.org/10.1016/j.jhep.2015.07.007Get rights and content

Background & Aims

It remains unclear whether diabetes increases the risk for hepatic encephalopathy (HE) in cirrhotic patients. We examined this question using data from three randomized trials of satavaptan, a vasopressin receptor antagonist that does not affect HE risk, in cirrhotic patients with ascites.

Methods

The trials included 1198 patients, and we excluded those with HE before or at randomization and followed the remaining patients for the one year duration of the trials. They were examined for HE regularly, and we compared rates of first-time overt HE between diabetics and non-diabetic patients using Cox regression, adjusting for gender, age, ascites severity, cirrhosis etiology, Child-Pugh class, creatinine, bilirubin, INR, sodium, potassium, albumin, platelets, lactulose use, benzodiazepine/barbiturate use, spironolactone dose, furosemide dose, potassium-sparing diuretic dose, and CirCom comorbidity score.

Results

We included 862 patients of whom 193 (22%) had diabetes. In total, they experienced 115 first-time episodes of overt HE during the follow-up. Fewer diabetics than non-diabetic patients were in Child-Pugh class C at baseline (13% vs. 23%), yet they had higher cumulative risk of first-time overt HE (26.0% vs. 15.8% after 1 year), and their episodes of first-time overt HE were more likely to progress beyond grade 2 (64% vs. 42% of episodes progressed to grade 3 or 4, p = 0.01 for independence between diabetes and highest HE grade). After the confounder adjustment, the hazard ratio of first-time overt HE for diabetics vs. non-diabetic patients was 1.86 (95% CI 1.20–2.87).

Conclusions

Diabetes increased the risk of first-time overt HE among cirrhotic patients with ascites.

Introduction

Clinically manifest hepatic encephalopathy (HE) is a very serious complication in liver cirrhosis. A marker of liver failure, its emergence is associated with an expected survival time of just a few months. Some cirrhotic patients are known to be at a greater risk of HE than others, particularly those with previous episodes, but also those with hyponatremia, poor metabolic liver function [1], or a transjugular intrahepatic portosystemic shunt (TIPS). In addition, diabetes mellitus has also been associated with a higher prevalence of HE [2], [3], [4], [5], although findings are not consistent [6]. Moreover, all previous studies addressing this question used a cross-sectional study design, meaning that they could not determine whether diabetes increased the incidence or the duration of HE episodes. Diabetes has never been examined as a risk factor for HE in a cohort study design.

There are good reasons to believe that diabetes favors HE development. Ammonia is taken to be the first hit in HE development, and diabetes induces glutaminase which via deamidation of glutamine releases ammonia [7]. Moreover, the insulin resistance inherent in cirrhotic diabetes favors muscle breakdown and ammonia production [7]. Diabetes may also increase bacterial translocation from the gut both by prolonging the intestinal transit time and causing bacterial overgrowth [8], and by modifying the gut microbiome [9]. This may lead to systemic inflammation, one of the most important second hits in HE development [10].

We had access to the complete original data from three randomized controlled trials of satavaptan treatment of ascites in patients with cirrhosis. Satavaptan, a vasopressin receptor antagonist, had no effect on the development of HE [11]. During the one year follow-up in these trials the participants were clinically examined for HE regularly, and their comorbidities, medications, and blood chemistry were recorded [12]. The aim of this analysis of the trial data was to examine whether diabetes increases the risk of first-time overt HE in cirrhotic patients with ascites.

Section snippets

Patients and methods

Between July 2006 and December 2008 three multinational randomized controlled trials were conducted to examine whether satavaptan was efficacious in treating ascites in cirrhotic patients. The three trials were conducted similarly but had different target populations: patients with diuretic-manageable ascites (N = 462), patients with ascites managed with diuretics and occasional therapeutic paracentesis (N = 496), and patients with diuretic-resistant ascites managed primarily with therapeutic

Results

We analyzed data from 862 cirrhotic patients, and 193 (22%) had diabetes, nearly all (96%) of type 2. Of the diabetic patients, 85 (44%) were treated with insulin, 25 (13%) with metformin, 36 (19%) with another oral antidiabetic drug, and 47 (24%) with diet alone. At study entry, 31% of patients had a serum sodium <135 mmol/L, and 7% <130 mmol/L. The total duration of follow-up was 539.4 person-years, with a median of 240 days per patient. During one year of follow-up 115 patients developed overt

Discussion

Our analysis of a large number of patients and their detailed data from three randomized trials showed that diabetes was a risk factor for first-time overt HE among cirrhotic patients with ascites. The diabetic patients’ HE episodes were no different from the non-diabetic patients’ in terms of precipitating factors, but they were of higher grade and developed earlier in the clinical course of cirrhosis. These findings are consistent with diabetes being an independent risk factor for HE

Financial support

PJ received funding from the Danish Council for Independent Research under the Danish Agency for Science, Technology and Innovation (10-081838/FSS).

Conflict of interest

HW is an employee of Sanofi. However, the analyses presented in this paper do not deal with any aspect of the Sanofi product investigated in these clinical studies. Neither are any conclusions reached nor recommendations made concerning any other Sanofi product. Therefore HW has no conflicts of interest to declare. PJ, PKA, and HV also have no conflicts of interest to declare.

Authors’ contributions

PJ, HW, and HV made substantial contributions to the study conception and acquisition of data. PJ and PKA conducted the statistical analysis. All authors contributed to the interpretation of data. PJ drafted the manuscript. All authors revised the manuscript for important intellectual content and approved the final manuscript.

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