Abnormal cholesterol metabolism underlies relative adrenal insufficiency in decompensated cirrhosis

Abstract

Background and Aims: Relative adrenal insufficiency (RAI) in patients with cirrhosis is associated with increased mortality. Although the pathogenesis of RAI remains unclear, disordered cholesterol metabolism may contribute. Methods:We performed a prospective cohort study of 96 non-critically ill subjects with decompensated cirrhosis at a tertiary care centre. Subjects were administered 250 µcg cosyntropin, with RAI defined as an increase in total cortisol <9 µg/dL. Highdensity lipoprotein (HDL) levels and serum cholesterol esterification percentage (%CE), a validated surrogate marker of lecithin-cholesterol acyltransferase (LCAT) activity, were measured to assess the relationship between disordered cholesterol metabolism and the presence of RAI. Subjects were followed until death, liver transplantation or a maximum of 6 months.Results: Subjects with RAI had decreased levels of HDL (18 vs 29 mg/dL, P < .01) and %CE (64% vs 66%, P = .03). Correlation was seen between HDL and %CE (r = 0.7, R 2 = 0.49; P < .01) and each integer decrease in %CE predicted an approximately 2% increase in the probability of RAI. Transplant-free survival was reduced in subjects with RAI at both 6 months (43% vs 71%, P = .01) and 90 days (54% vs 81%, P < .01). Conclusions:Disruption in cholesterol metabolism contributes to the development of RAI in cirrhosis, as decreased LCAT activity leads to reduced HDL trafficking to the adrenal gland.

How I Approach It: Adrenal Insufficiency in Cirrhosis

“…Given these drawbacks, ACTH stimulation testing with TC levels continues to be the preferred diagnostic strategy to assess for AI in patients with cirrhosis given widespread clinical availability and rapid performance characteristics. Recent literature suggests adoption of delta cortisol rather than peak cortisol to diagnose RAI in cirrhosis because it implies a poor short-to-medium term prognosis, is less dependent on basal cortisol levels, and may provide a better assessment of adrenal responsiveness to acute stimuli (1,2,4). Free cortisol levels, if available, may be simultaneously obtained with TC levels to assess for underlying basal cortisol deficiency, although results may take up to 1–2 weeks given samples are often sent to an outside reference laboratory (1).…”

“…Current pathophysiologic understanding of AI in cirrhosis is incomplete but may be multifactorial (1). Identified associations with abnormal cortisol responses in cirrhosis and inflammatory states include low HDL levels (adrenal substrate for steroidogenesis), decreased corticosteroid-binding globulin, and increased proinflammatory cytokines (including TNFa, IL-1, and IL-6), but their causality is not firmly established (1,3,9). Whether perturbations elsewhere along the HPA axis, adrenal enzymatic activity and/or steroidogenic pathway shunting, or dysregulation of systemic vascular tone contribute to RAI remain unknown (Figure 2).…”

“…Initially identified in critically ill patients (the "hepatoadrenal syndrome"), this phenomenon also extends to the noncritically ill population and is characterized by inadequate adrenal reserve in relation to physiologic demands (1)(2)(3)(4). Current pathophysiologic understanding of AI in cirrhosis is incomplete but may be multifactorial (1). Identified associations with abnormal cortisol responses in cirrhosis and inflammatory states include low HDL levels (adrenal substrate for steroidogenesis), decreased corticosteroid-binding globulin, and increased proinflammatory cytokines (including TNFa, IL-1, and IL-6), but their causality is not firmly established (1,3,9).…”

“…Despite these issues, societal guidelines offer little direction in this population, leading to confusion and uncertainty regarding diagnostic and management best practices (8). In addition, discrimination between a basal cortisol deficiency and a stress-induced relative cortisol deficiency is paramount but inconsistently applied (1). Recognizing this significant gap between the literature and patient care, this primer provides clinicians with a practical approach to a common problem.…”

The Clinical Significance of Lipids/Lipoproteins Impairment in the Context of Cirrhosis: An Updated Review

“…55 Furthermore, Wentworth et al have demonstrated that decreased HDL-C levels and diminished lecithincholesterol acyltransferase activity partially account for the development of RAI in decompensated cirrhotic patients. 56 They proposed that cholesterol metabolism impairment results in inadequate substrate delivery to the adrenal gland, which is responsible for normal steroidogenesis.…”