Relative adrenal insufficiency in the non‐critically ill patient with cirrhosis: A systematic review and meta‐analysis

Abstract

Background & Aims Characterization of relative adrenal insufficiency (RAI) in cirrhosis is heterogeneous with regard to studied patient populations and diagnostic methodology. We aimed to describe the prevalence and prognostic importance of RAI in non‐critically ill patients with cirrhosis. Methods A systematic review and meta‐analysis was performed using MeSH terms and Boolean operators to search five large databases (Ovid‐MEDLINE, ScienceDirect, Web of Science, Cochrane Library and http://clinicaltrials.gov). The population of interest was patients with cirrhosis and without critical illness. The primary outcome was the pooled prevalence of RAI as defined by a peak total cortisol level <18 μg/dl, delta total cortisol <9 μg/dl or composite of the two thresholds in response either a standard‐dose or low‐dose short synacthen test. Odds ratios and standardized mean differences from random‐effects models estimated important clinical outcomes and patient characteristics by adrenal functional status. Results Twenty‐two studies were included in final analysis, comprising 1991 patients with cirrhosis. The pooled prevalence of RAI was 37% (95% CI 33–42%). The prevalence of RAI varied by Child–Pugh classification, type of stimulation test used, specific diagnostic threshold and by severity of illness. Ninety‐day mortality was significantly higher in patients with RAI (OR 2.88, 95% CI 1.69–4.92, I2 = 15%, p < 0.001). Conclusions Relative adrenal insufficiency is highly prevalent in non‐critically ill patients with cirrhosis and associated with increased mortality. Despite the proposed multifactorial pathogenesis, no studies to date have investigated therapeutic interventions in this specific population.

Author's reply: Plasma corticosteroid‐binding globulin levels in cirrhosis

“…Interestingly, prior literature has shown that TC levels correlate well with both plasma free cortisol and salivary cortisol levels in patients with cirrhosis, even in patients with moderate to severe hypoalbuminemia. 3,4 Coupled with our finding that subnormal Cosyntropin stimulation responses are associated with a nearly three-fold increased risk of 90-day mortality, 1 early identification of RAI in cirrhosis appears to be more clinically relevant than precise bioactive cortisol measurement.…”

“…lighted by variance in prevalence estimates depending on methodology, exposition of which was a primary aim of our manuscript. 1 However, binding-globulin independent cortisol forms (i.e., salivary or plasma free cortisol), are not routinely available to clinicians and thus provide lower practical utility. Interestingly, prior literature has shown that TC levels correlate well with both plasma free cortisol and salivary cortisol levels in patients with cirrhosis, even in patients with moderate to severe hypoalbuminemia.…”

Plasma corticosteroid‐binding globulin concentrations are preserved in mild cirrhosis

“…We have read with interest the review by BJ Wentworth et al, 1 which assessed cortisol in 22 studies of patients with stable cirrhosis, mostly by standard dose cosyntropin stimulation tests. They reported a high incidence of reduced peak or delta cortisol postcosyntropin, 29% and 36% respectively.…”

“…The prevalence of relative adrenal insufficiency positively correlated with disease severity defined by Childs Pugh score. 1 Corticosteroid-binding globulin (CBG) was not measured.…”

Basal cortisol levels do not predict adrenal responsiveness in acute decompensated cirrhosis

“…Adrenal dysfunction (AD) is common in cirrhosis but infrequently diagnosed in clinical practice [1]. Its prevalence correlates with the severity of underlying liver disease and carries prognostic implications [2,3]. Multiple studies demonstrate that an abnormal cortisol stimulation response is associated with an increased risk of short-to-medium-term mortality, independent of the underlying liver disease [4][5][6][7].…”