Reduced cortisol metabolism during critical illness

Abstract

Background: Critical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism.

Methods: In a total of 158 patients in the intensive care unit and 64 matched controls, we tested five aspects of cortisol metabolism: daily levels of corticotropin and cortisol; plasma cortisol clearance, metabolism, and production during infusion of deuterium-labeled steroid hormones as tracers; plasma clearance of 100 mg of hydrocortisone; levels of urinary cortisol metabolites; and levels of messenger RNA and protein in liver and adipose tissue, to assess major cortisol-metabolizing enzymes.

Results: Total and free circulating cortisol levels were consistently higher in the patients than in controls, whereas corticotropin levels were lower (P<0.001 for both comparisons). Cortisol production was 83% higher in the patients (P=0.02). There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg of hydrocortisone in the patients (P≤0.03 for both comparisons). All these factors accounted for an increase by a factor of 3.5 in plasma cortisol levels in the patients, as compared with controls (P<0.001). Impaired cortisol clearance also correlated with a lower cortisol response to corticotropin stimulation. Reduced cortisol metabolism was associated with reduced inactivation of cortisol in the liver and kidney, as suggested by urinary steroid ratios, tracer kinetics, and assessment of liver-biopsy samples (P≤0.004 for all comparisons).

Conclusions: During critical illness, reduced cortisol breakdown, related to suppressed expression and activity of cortisol-metabolizing enzymes, contributed to hypercortisolemia and hence corticotropin suppression. The diagnostic and therapeutic implications for critically ill patients are unknown. (Funded by the Belgian Fund for Scientific Research and others; ClinicalTrials.gov numbers, NCT00512122 and NCT00115479; and Current Controlled Trials numbers, ISRCTN49433936, ISRCTN49306926, and ISRCTN08083905.).

Figure 1. Dissociation between Corticotropin and Cortisol Levels among Patients in the Intensive Care Unit (ICU)

Shown are mean values for cortisol (Panel A) and corticotropin (Panel B) in 47 patients from day 1 to day 7 in the ICU. The shaded area represents the interquartile range of values in 12 healthy controls. The overall mean cortisol levels over the 7-day period were 16.8±7.8 μg per deciliter (464±215 nmol per liter) for patients and 11.9±2.3 μg per deciliter (328±63 nmol per liter) for controls (P=0.01). The overall mean corticotropin levels over the 7-day period were 16.9±9.5 pg per milliliter (4±2 pmol per liter) for patients and 49.6±37.9 pg per milliliter (11±8 pmol per liter) for controls (P<0.001). To convert values for cortisol to nanomoles per liter, multiply by 27.6. To convert values for corticotropin to picomoles per liter, multiply by 0.22. The I bars indicate standard errors.

Figure 2. Results of Infusion of D4-Cortisol Tracer

Shown are mean plasma levels of endogenous cortisol (Panel A) and D4-cortisol tracer (Panel B), which reached steady state during the study period, in 11 patients and 9 controls. The I bars indicate standard errors. To convert values for D4-cortisol to nanomoles per liter, multiply by 27.3. Also shown are the mean rate of appearance of cortisol (Panel C), mean preinfusion plasma corticotropin levels (Panel D), and mean D4-cortisol clearance (Panel E). In Panels C, D, and E, the T bars indicate standard errors. Plasma clearance of D4-cortisol (Panel F) and the rate of appearance of cortisol (Panel G) were correlated with plasma cortisol responses, measured for 60 minutes after the injection of corticotropin (250 μg) in the patients. In Panels F and G, the red lines indicate the regression lines, and the shaded areas represent 95% confidence intervals.

Figure 3. Activity of Cortisol-Metabolizing Enzymes, as Estimated from Ratios of Cortisol Metabolites in 24-Hour Urine Samples

Enzyme activities were estimated in 36 patients and 15 controls on the basis of urinary metabolites quantified with the use of gas chromatography–mass spectrometry. The overall activity of 11β-hydroxysteroid dehydrogenases (11β-HSDs) was calculated as the ratio of a combination of 5α-tetrahydrocortisol and 5β-tetrahydrocortisol to tetrahydrocortisone (Panel A), which reflects the relative balance of the cortisone–cortisol interconversion. The activity of renal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) was estimated by calculating the ratio of cortisone to cortisol (Panel B). The activity of 5α-reductase was estimated by calculating the ratio of 5α-tetrahydrocortisol to cortisol (Panel C). The activity of 5β-reductase was estimated by calculating the ratio of 5β-tetrahydrocortisol to cortisol (in Panel D) and the ratio of tetrahydrocortisone to cortisone (Panel E). In Panels A through E, the bars represent means, and the T bars standard errors. The lower panels show the correlations of the level of total bile acids (in log₁₀ values) with the activity of 5α-reductase as estimated by calculating the ratio of 5α-tetrahydrocortisol to cortisol (Panel F), the activity of 5β-reductase activity as estimated by calculating the ratio of 5β-tetrahydrocortisol to cortisol (Panel G), and the activity of 5β-reductase as estimated by calculating the ratio of tetrahydrocortisone to cortisone (Panel H). The red lines in the three lower panels indicate the regression lines, and the shaded areas represent 95% confidence intervals.

Figure 4. Tissue Expression of Cortisol-Metabolizing Enzymes in Relation to Circulating Levels of Cortisol and Bile Acids

Shown are the results, for 44 patients and 20 controls, of studies evaluating total bile acids (Panel A), 5β-reductase messenger RNA (mRNA) (Panel B), and 5β-reductase protein (Panel C). In Panels A, B, and C, the bars represent means, and the T bars standard errors. The lower panels show the correlations of the 5β-reductase protein level or total bile acid level (in log₁₀ values) with the plasma level of cortisol (Panel D), 5β-reductase mRNA (Panel E), and 5β-reductase protein (Panel F). The red lines in the three lower panels indicate regression lines, and the shaded areas represent 95% confidence intervals. The mRNA data, which have been normalized for glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) expression, are expressed as the factor difference from the mean value for the controls. The protein data, which have been normalized for cytokeratin 18 protein expression, are also expressed as the factor difference from the mean value for the controls.