β-blockade in liver cirrhosis: effects on energy metabolism and glucose tolerance

Abstract

Aims: Liver cirrhosis is a common cause of morbidity and mortality. Elevated resting energy expenditure (REE) is associated with a poorer outcome, even within the normal range of REE. β- blockers are commonly taken by patients with liver cirrhosis for the prevention of variceal haemorrhage and these patients are less likely to have an elevated REE. The primary aim of this thesis was to determine if treatment with nadolol (non-cardioselective β-blocker) reduced REE and if the treatment resulted in detrimental effects on the insulin sensitivity, β-cell function and glucose tolerance of patients with liver cirrhosis who have an existing predisposition for impaired glucose metabolism. Methods: The published literature was systematically reviewed to determine the prevalence of diabetes in patients with liver cirrhosis according to aetiology and other sources of potential variation. Analysis and reporting of the systematic review was based initially on the QUORUM and subsequently the PRISMA guidelines. In a double-blind, randomised, controlled, cross-over trial, 23 stable patients with liver cirrhosis not already taking β-blockers were randomly allocated to 3-month treatment with nadolol (titrated to decrease resting pulse rate by 20% or to below 60 beats per minute) or visually-identical placebo. After a 1-month washout period these patients were crossed to the alternate treatment for a further 3 months. Changes in REE, body composition, insulin sensitivity, β-cell function and glucose tolerance were measured at the beginning and the end of each period of treatment. Insulin sensitivity, β-cell function and glucose tolerance were also measured in 6 healthy volunteers. REE was measured by indirect calorimetry using a ventilated hood. Patients were rested for at least 30min in a thermoneutral environment prior to measurement of REE. Concurrently, total body protein (TBP) was derived from measurement of total body nitrogen using prompt- in vivo neutron activation analysis while total body fat and fat free mass (FFM) was derived by software analysis of whole-body dual-energy X-ray absorptiometry (DEXA) scanning. Insulin sensitivity was measured using the gold standard hyperinsulinaemic euglycaemic clamp (which was used to derive the insulin sensitivity index adjusted for FFM (ISIFFM), combined with an intravenous glucose tolerance test (IVGTT) to allow concurrent measurement of β-cell function. In addition to the IVGTT, β-cell function was also measured using the disposition index, and a mathematical model for β-cell function (Mari model) derived from glucose, insulin and C-peptide measurements during a standard 75g 2 hour oral glucose tolerance test (OGTT). Insulin secretion in the β-cell function model was derived by C-peptide deconvolution due to the variable kinetics of insulin metabolism that may be more profound in patients with liver cirrhosis. Glucose tolerance was also determined from the OGTT using the 2006 World Health Organisation guidelines. Findings: Diabetes was most prevalent in patients with cryptogenic, hepatitis C (HCV) and alcoholic cirrhosis. REE did not differ significantly on nadolol and placebo due to the study sample of mainly compensated patients with normal REE. Nevertheless, REE during treatment with nadolol was reduced compared to baseline and the reduction correlated with both baseline REE, and the degree by which REE was elevated over expected REE. Nadolol reduced the insulin sensitivity and β-cell function of the patients but the small size of the study precluded demonstrating a significant reduction in glucose tolerance. Unexpectedly, an early increase in β-cell function of compensated cirrhotic patients with normal insulin sensitivity was observed when compared to healthy volunteers. Conclusions: β-blockade may have a role in reducing REE in cirrhotic patients with an abnormally elevated REE although a lack of effect was seen in this cohort of primarily normometabolic patients. However, the potential benefit of this treatment needs to be balanced against the detrimental effects on the insulin sensitivity and β-cell function of these patients which may lead to a poorer outcome. Lastly, an increase in β-cell function may precede and possibly even precipitate the reduction of insulin sensitivity in patients with liver cirrhosis but these findings will need to be confirmed in a larger and more representative cohort of patients.