S1266 Elevated Interleukin-6 Activity Is Associated With Adrenal Insufficiency in Outpatients With Decompensated Cirrhosis

Abstract

Introduction: Inflammatory cytokines are known to suppress hypothalamic-pituitary-adrenal (HPA) axis activity. While cytokine levels are elevated in patients with cirrhosis, prior literature has not demonstrated an association between cytokine activity and adrenal gland dysfunction. Moreover, these prior studies investigated hospitalized patients whose HPA axis is confounded by acute illness. As the pathophysiology of adrenal insufficiency (AI) in cirrhosis remains incompletely defined, we undertook a prospective study in outpatients to determine if there exists a differential cytokine profile in the absence of acute illness. Methods: Adult patients with decompensated cirrhosis (Child-Pugh B [CP-B] or C [CP-C]) were recruited from outpatient clinics. Recent alcohol use or medications known to affect the HPA axis were grounds for exclusion. Study participants had standard laboratory chemistries drawn as well as an ACTH level. Thirteen 13 cytokine levels (IL-1a, IL-1b, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17A, IL-18, IFNγ, TNFa) were assessed to encompass a diverse picture of immune system function. Cytokine analysis was performed using the Luminex multiplex immunoassay. Participants then underwent a standard-dose (250µg) cosyntropin stimulation test with AI being defined as an increase in total cortisol level of < 9 µg/dL. All labs and testing were performed between 8-11 AM. Comparative analyses utilized the Mann-Whitney-U test. Results: Interim analysis of 34 participants revealed a median MELD of 12 (26 CP-B, 8 CP-C). Thirteen participants (38%) met AI criteria; 50% of all CP-C participants (n=4) had RAI vs. 35% of all CP-B (n=9) participants. Baseline characteristics between AI and non-AI groups with respect to disease etiology and severity were similar, as were ACTH levels (13 pg/mL vs. 16 pg/mL, p = 1.000). Cytokine analysis revealed significantly higher IL-6 levels in patients with AI (24.12 pg/mL vs. 12.29 pg/mL, p = 0.046). Conclusion: In this hypothesis-generating study, elevated IL-6 levels were associated with the presence of AI in cirrhosis. This raises two possibilities: whether IL-6 suppresses ACTH release (given low-normal levels were found in patients with AI) or whether IL-6 is increased secondary to low circulating cortisol levels (as cortisol inhibits inflammation). Our findings suggest IL-6 may be a useful biomarker for AI in cirrhosis but further research is needed to elucidate its effects. (Table) Table 1. - Cytokine level analysis between normal and adrenally insufficient outpatients with cirrhosis Normal adrenal function (n = 21) Adrenal insufficiency (n = 13) P-value IL-1a (pg/mL) 4.56 (4.51, 17.02) 4.51 (4.51, 15.46) 0.771 IL-1b (pg/mL) 38.75 (12.05, 95.52) 29.75 (10.05, 58.97) 0.645 IL-1RA (pg/mL) 18.43 (13.70, 30.59) 14.16 (8.6, 21.05) 0.357 IL-2 (pg/mL) 5.34 (0.62, 21.53) 5.20 (0.74, 18.48) 0.800 IL-4 (pg/mL) 0.28 (0.28, 7.33) 0.28 (0.28, 4.75) 0.897 IL-5 (pg/mL) 2.89 (1.48, 15.69) 4.55 (2.14, 7.11) 0.954 IL-6 (pg/mL) 12.29 (5.47, 23.57) 24.12 (15.10, 38.91) 0.046 IL-8 (pg/mL) 49.65 (28.24, 81.67) 33.35 (27.51, 60.68) 0.466 IL-10 (pg/mL) 14.91 (8.28, 36.56) 24.64 (13.64, 35.34) 0.378 IL-17A (pg/mL) 10.74 (2.04, 52.78) 5.29 (0.43, 33.00) 0.817 IL-18 (pg/mL) 34.86 (27.71, 69.14) 34.50 (16.01, 57.58) 0.848 IFNγ (pg/mL) 10.78 (1.62, 33.71) 12.43 (2.59, 30.89) 0.659 TNFa (pg/mL) 37.14 (13.94, 108.75) 33.66 (17.25, 69.97) 0.759 IL - interleukin, IFN - interferon, TNF - tumor necrosis factor.