Changes in the 24-h plasma cortisol rhythm in patients with cirrhosis
Authors: Sara Montagnese, Benita Middleton, Ali R. Mani, Debra J. Skene, Marsha Y. Morgan
Journal: Journal of Hepatology (2010)

Assessment of adrenal function in cirrhotic patients: Salivary cortisol should be preferredJournal of HepatologyVol. 52Issue 6PreviewAdrenal insufficiency is a common disorder among cirrhotic patients. Adrenal function is usually assessed with serum total cortisol assays. Free cortisol (active fraction) represents only 10% of serum total cortisol, the remaining 90% being linked to cortisol-binding globulin (CBG) and albumin. In cirrhotic patients, the synthesis of these proteins is reduced, which could lead to an overestimation of the prevalence of adrenal insufficiency. Salivary cortisol assessment adequately reflects free cortisol plasma concentration. Full-Text PDF Adrenal insufficiency: Diagnosis in patients with liver cirrhosis is difficultJournal of HepatologyVol. 54Issue 3PreviewWe were very interested by the letter of Montagnese et al. published in this issue of the Journal of Hepatology [1]. Many recent publications led us to believe that adrenal insufficiency, assessed by serum total cortisol assays, was very common in patients with liver cirrhosis [2–7]. In fact, cortisol transport proteins (cortisol binding globulin and albumin) are often decreased in patients with cirrhosis, leading to a reduced bound fraction of cortisol, whereas free cortisol concentration, which is the active fraction of cortisol, remains unchanged. Full-Text PDF Open Access To the Editor: We read with interest the recent study by Galbois and colleagues [[1]Galbois A. Rudler M. Massard J. Fulla Y. Bennani A. Bonnefont-Rousselot D. et al.Assessment of adrenal function in cirrhotic patients: salivary cortisol should be preferred.J Hepatol. 2010; 52: 839-845Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar], which showed that the measurement of total serum cortisol considerably overestimates the prevalence of hepato-adrenal syndrome because the bound fraction of cortisol may be reduced in the presence of cirrhosis, while the more important free cortisol fraction is unchanged. We would like to report on how abnormalities in the 24-h rhythm of cortisol may also confound the diagnosis of adrenal insufficiency in this patient population. Twenty outpatients with biopsy-proven cirrhosis [mean (±SD) age 59 ± 11 yr; Child’s grade A: n = 14, B: 4, C: 2] and nine healthy volunteers (60 ± 14 yr) were studied in a sleep laboratory under light-controlled conditions [2]. Venous blood samples for the measurement of plasma free cortisol (PFC) concentrations were obtained hourly between 18:00 and 10:00 and two-hourly between 10:00 and 18:00. PFC was measured using a radioimmunoassay [[3]Read G.F. Fahmy D.R. Walker R.F. Determination of cortisol in human plasma by radioimmunoassay. Use of the 125I-labelled radioligand.Ann Clin Biochem. 1977; 14: 343-349Crossref PubMed Scopus (20) Google Scholar]. Absolute PFC values at 08.00 (‘morning cortisol’) were obtained for each subject. Means of the five lowest/highest PFC concentrations over the 24 h were also obtained. The mathematical difference between the mean of the five lowest and the five highest values, or range, was calculated. The onset and offset of the PFC rhythm were defined as the time points, on the rise and fall of the concentration–time curve, when the plasma concentrations equalled 25% of the peak concentration [[4]Gogenur I. Ocak U. Altunpinar O. Middleton B. Skene D.J. Rosenberg J. Disturbances in melatonin, cortisol and core body temperature rhythms after major surgery.World J Surg. 2007; 31: 290-298Crossref PubMed Scopus (58) Google Scholar]; the time interval between rhythm onset and offset was termed peak duration. Visual analysis of the 24-h PFC concentration–time curves (Fig. 1) revealed a morning ‘double-peak’ in both the healthy volunteers and the patients with cirrhosis. However, the timing of the PFC peak in the patients was considerably delayed (Fig. 1). This feature was more prominent in patients with Child’s B/C cirrhosis (Fig. 2).Fig. 2Plasma free cortisol (PFC) 24-h concentration-time curves in patients with Child’s A cirrhosis (black circles) and patients with Child’s B/C cirrhosis (grey triangles). Patients with Child’s B/C cirrhosis showed a more prominent delay in the timing of the cortisol peak compared to their counterparts with Child’s A cirrhosis, although statistical significance was not reached.View Large Image Figure ViewerDownload Hi-res image Download (PPT) No differences were observed in mean PFC values at 08:00 between patients and healthy volunteers (212 ± 102 vs. 171 ± 67 nmol/L, p= 0.29), most likely reflecting the shape of the PFC concentration–time curves and the considerable variability of cortisol concentrations over the morning hours (Fig. 1). Similarly, no significant differences were observed in the average five lowest/highest PFC concentrations (51 ± 19 vs. 53 ± 12 nmol/L, p= 0.60; 248 ± 76 vs. 211 ± 37 nmol/L, p= 0.20) or the PFC range (196 ± 73 vs. 157 ± 34 nmol/L, p= 0.12). A PFC rhythm onset could be identified in all subjects; it was significantly delayed in the patients compared with the healthy volunteers (05:24 ± 02:06 vs. 03:54 ± 01:00, p= 0.02, Fig. 1). In two (22%) healthy volunteers and seven (35%) patients the rhythm offset occurred after 18:00, beyond sampling time, thus the parameters offset and duration could not be obtained. In the 13 patients and seven healthy volunteers in whom these parameters were obtained, no significant difference was observed in the timing of the rhythm offset between the two groups but the duration of the peak was significantly shorter in the patients (7.0 ± 3.8 vs. 10.6 ± 2.3 h, p= 0.03). Patients with Child’s B/C cirrhosis had significantly lower 08.00 PFC values compared to their counterparts with Child’s A cirrhosis (135 ± 42 vs. 246 ± 103 nmol/L, p= 0.04). In addition, they had a higher mean of the five lowest PFC concentrations (61 ± 12 vs. 48 ± 20 nmol/L, p= 0.05), a lower, although not significantly different, mean of the five highest PFC concentrations (208 ± 74 vs. 264 ± 72 nmol/L, p= 0.12) and, in consequence, a lower range (148 ± 75 vs. 217 ± 63 nmol/L, p= 0.04). In addition, a direct correlation was observed between the means of the five lowest PFC concentrations and the Pugh’s score (R = 0.64, p<0.01). Both the PFC rhythm onset and offset were delayed in patients with Child’s B/C compared to those with Child’s A cirrhosis (Fig. 2) but the differences did not reach statistical significance (onset 06:12 ± 01:48 vs. 05:06 ± 02:12, p= 0.28; offset 13:48 ± 02:42 vs. 12:00 ± 03:00, p= 0.37). A considerable delay in the onset of the cortisol rhythm and abnormalities in the duration of the peak were observed in this patient series, in parallel with the degree of hepatic dysfunction. While the exact pathophysiology of cortisol timing alterations in patients with cirrhosis is unknown, they are most likely cerebral in origin. Cortisol, like melatonin, is a direct marker of the phase of the hypothalamic clock, which regulates the diurnal rhythm of circadian hormones in relation to light and dark cues. It has previously been shown that patients with cirrhosis exhibit abnormalities in the sensitivity of the hypothalamic clock to light [[2]Montagnese S. Middleton B. Mani A.R. Skene D.J. Morgan M.Y. On the origin and the consequences of circadian abnormalities in patients with cirrhosis.Am J Gastroenterol. 2010; 105: 1773-1781Crossref PubMed Scopus (60) Google Scholar], which may explain abnormalities in both melatonin and cortisol rhythms [[5]Boivin D.B. Czeisler C.A. Resetting of circadian melatonin and cortisol rhythms in humans by ordinary room light.Neuroreport. 1998; 9: 779-782Crossref PubMed Scopus (114) Google Scholar]. The patients with decompensated cirrhosis had significantly lower PFC values at 08.00 and less variation in PFC values over the 24 h compared to their compensated counterparts. These findings might relate to: (i) adrenal insufficiency per se; (ii) abnormalities of cortisol metabolism, which could be responsible for the increase in the low PFC values; or (iii) sympathetic–parasympathetic imbalance, which could affect the patients’ ability to modulate cortisol responses to external stimuli. The strength of the present series is that cortisol 24-h rhythms were estimated under ‘ideal’ conditions, namely: (i) the measurement of PFC, which is not affected by albumin concentrations and, (ii) the exercise of tight controls for light exposure, which is known to phase-reset the cortisol rhythm, thus affecting its timing, via the hypothalamic clock [[5]Boivin D.B. Czeisler C.A. Resetting of circadian melatonin and cortisol rhythms in humans by ordinary room light.Neuroreport. 1998; 9: 779-782Crossref PubMed Scopus (114) Google Scholar]. The weakness is that most of the patients studied had compensated cirrhosis, whereas adrenal insufficiency is observed most frequently in those with decompensated disease and sepsis. However, the characteristics of the cortisol rhythms in the six patients with Child’s B/C cirrhosis suggest that even more pronounced rhythm timing/amplitude abnormalities might be present in patients with more severe liver dysfunction. It has recently been suggested that morning basal cortisol could be useful to identify patients with cirrhosis at high risk for adrenal insufficiency [[6]Fede G. Spadaro L. Tomaselli T. Privitera G. O’Beirne J. Garcovich M. et al.Assessment of adrenocortical reserve in stable patients with cirrhosis.J Hepatol. 2010; 52: S71-S72Abstract Full Text PDF Google Scholar]. However, it seems extremely unlikely that isolated morning total or even free plasma cortisol samples could be used as a stand-alone diagnostic index because of the observed delay in cortisol rhythm onset and the shape of the cortisol peak. This, together with the recently published data on the potential drawbacks of measuring plasma total cortisol in this patient population [[1]Galbois A. Rudler M. Massard J. Fulla Y. Bennani A. Bonnefont-Rousselot D. et al.Assessment of adrenal function in cirrhotic patients: salivary cortisol should be preferred.J Hepatol. 2010; 52: 839-845Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar], indicates that the diagnosis of hepato-adrenal syndrome might be more complex than previously believed. It may, for example, necessitate a free cortisol corticotropin test and, possibly, an assessment of the circadian phase using, for example, an evening melatonin measurement. Further studies are needed to devise a model whereby baseline/stimulated cortisol concentrations can then be adjusted for the patients’ circadian phase. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.