Adrenal insufficiency in liver diseases - pathophysiology and underlying mechanisms.

Relative adrenal insufficiency (RAI) is common in critically ill patients with cirrhosis, but it has been also documented in non-critically ill patients. Its pathophysiology is complex and not well understood yet. In this review, we aimed to present potential mechanisms and causal pathways implicated in the pathogenesis of RAI in cirrhosis. There is accumulating evidence supporting a suboptimal baseline adrenal function in cirrhosis mainly due to decreased cortisol synthesis and metabolism rates from the adrenal gland. Apart from this peripheral impairment, more recent studies suggest that there is a greater defect in the central stimulation of the hypothalamic-pituitary-adrenal (HPA) axis (hypothalamus/pituitary gland). Pro-inflammatory mediators, which are elevated in cirrhosis, have been also implicated through suppression of the HPA axis, decrease in cortisol synthesis and tissue glucocorticoid resistance. All abovementioned support the hepatoadrenal syndrome hypothesis that during episodes of acute decompensation there is suboptimal adrenocortical response that leads to worse outcomes. In conclusion, the complex pathophysiology of adrenal dysfunction in cirrhosis has not been fully elucidated yet and further research is needed in order to better understand this rather common entity in cirrhosis.

Salivary Cortisol Measurement Contamination After Oral Hydrocortisone: A Randomized Crossover Trial.

The study aimed to evaluate salivary cortisol (SC) contamination and determine the associated factors in secondary adrenal insufficiency (SAI) patients treated with hydrocortisone (Hc). A randomized crossover trial involved SAI patients. SC was measured before the morning Hc dose, then at one, two, and four hours after. The procedure was performed twice on two days of a week: one day while taking Hc in tablet form (tablet set) and one day while taking Hc in capsule form (capsule set). Area under the curve (AUC) of SC levels over time was calculated in each participant for the two sets. SC contamination was defined as AUCtablet above the 95th percentile of AUCcapsule. Thirty-four patients (24 females and 10 males) with a median age of 48 years were enrolled. Post-Hc dose SC levels were higher in tablet than in capsule set, particularly at one hour. Prevalence and extent of SC contamination were estimated to 32% and 88%, respectively. In capsule set, SC measured two hours after Hc intake showed the strongest correlation with AUC (r=0.88, p<0.001). In multivariate analysis, serum potassium≥3.9 mEq/l was the only predictor for SC contamination [multi-adjusted OR (95% CI): 7.1 (1.4-36.1); p=0.018]. SC measured during the two hours after Hc intake is inaccurate for glucocorticoid replacement therapy assessment in SAI patients treated with Hc in tablet form.

Novel agents to treat adrenal insufficiency: findings of preclinical and early clinical trials.

INTRODUCTION: Adrenal insufficiency currently affects over 300/million population, with higher morbidity and mortality compared to the general population. Current glucocorticoid replacement therapy is limited by a lack of reliable biomarkers to guide dosing, inter-patient variation in metabolism and narrow therapeutic window. Increased morbidity and mortality may relate to unappreciated under- or over-exposure to glucocorticoids and impaired cortisol circadian rhythm. New agents are required to emulate physiological cortisol secretion and individualize glucocorticoid dosing. AREAS COVERED: History of glucocorticoid therapy, current limitations, and novel chronotherapeutic glucocorticoid delivery mechanisms. Literature search incorporated searches of PubMed and Embase utilizing terms such as adrenal insufficiency, Chronocort, Plenadren, continuous subcutaneous hydrocortisone infusion (CHSI), and glucocorticoid receptor modulator. EXPERT OPINION: Glucocorticoid chronotherapy is necessary to optimize glucocorticoid exposure and minimize complications. Current oral chronotherapeutics provide improved dosing functionality, but are modifiable only in specific increments and cannot accommodate ultradian cortisol variation. Current data show improvement in quality of life but not morbidity or mortality outcomes. CHSI has significant potential for individualized glucocorticoid dosing, but would require a suitable biomarker of glucocorticoid adequacy to be implementable. Avenues for future research include determining a glucocorticoid sufficiency biomarker, development of interstitial or systemic cortisol monitoring, or development of glucocorticoid receptor modulators.

Salivary Cortisol and Cortisone Can Circumvent Confounding Effects of Oral Contraceptives in the Short Synacthen Test.

CONTEXT: Adrenal insufficiency (AI) is usually diagnosed by low plasma cortisol levels following a short Synacthen test (SST). Most plasma cortisol is bound to corticosteroid-binding globulin, which is increased by estrogen in combined estrogen-progestin oral contraceptives (COCs). Women with AI using COCs are therefore at risk of having an apparently normal plasma cortisol level during SST, which would not adequately reflect AI. OBJECTIVE: This work aimed to test whether salivary cortisol or cortisone during SST is more robust against the COC effect and to calculate the lower reference limits (LRLs) for these to be used as tentative diagnostic cutoffs to exclude AI. METHODS: Forty-one healthy women on COCs and 46 healthy women without exogenous estrogens underwent an SST with collection of plasma and salivary samples at 0, 30, and 60 minutes after Synacthen injection. The groups were compared using regression analysis with age as covariate and the LRLs were calculated parametrically. RESULTS: SST-stimulated plasma cortisol levels were significantly higher in the COC group vs controls, while mean salivary cortisol and cortisone levels were slightly lower in the COC group. Importantly, COC use did not significantly alter LRLs for salivary cortisol or cortisone. The smallest LRL difference between groups was seen for salivary cortisone. CONCLUSION: Salivary cortisol and especially salivary cortisone are considerably less affected by COC use than plasma cortisol during SST. Due to similar LRLs, a common cutoff for salivary cortisol and cortisone during SST can be used to exclude AI in premenopausal women irrespective of COC use.

Clinical spectrum of human STAR variants and their genotype-phenotype correlation.

Biallelic variants of steroidogenic acute regulatory protein (STAR/STARD1) may cause primary adrenal insufficiency and 46,XY disorder of sex development. STAR plays a pivotal role in transporting cholesterol into mitochondria where cholesterol serves as an essential substrate for initiating steroid biosynthesis by its conversion to pregnenolone. Generally, loss-of-function mutations of STAR cause the classic form of lipoid congenital adrenal hyperplasia (LCAH) where steroidogenesis of the adrenal cortex and the gonads is severely affected. By contrast, partial activity of STAR causes a less severe phenotype, the non-classic LCAH, which is characterized by later onset and initial manifestation with isolated adrenal insufficiency only. Disease-causing STAR variants are very rare. Numerous variants of all types have been described worldwide. Prevailing variants have been reported from Japan and Korea and in some population clusters where STAR is more common. Genotype-phenotype correlation is pretty good for STAR variants. While the exact mechanisms of cholesterol transport into mitochondria for steroidogenesis are still under investigation, the important role of STAR in this process is evident by inactivating STAR variants causing LCAH. The mechanism of disease with STAR deficiency is best described by a two-hit model: the first hit relates to impaired cholesterol import into mitochondria and thus lack of substrate for all steroid hormone biosynthesis; the second hit then relates to massive cytoplasmic lipid overload (evidenced by typically enlarged and fatty adrenal glands) leading to cell death and organ destruction. This review summarizes phenotype and genotype characteristics of human STAR variants found through the ClinVar database.

FDXR variants cause adrenal insufficiency and atypical sexual development.

Genetic defects affecting steroid biosynthesis cause cortisol deficiency and differences of sex development; among these defects are recessive mutations in the steroidogenic enzymes CYP11A1 and CYP11B, whose function is supported by reducing equivalents donated by ferredoxin reductase (FDXR) and ferredoxin. So far, mutations in the mitochondrial flavoprotein FDXR have been associated with a progressive neuropathic mitochondriopathy named FDXR-related mitochondriopathy (FRM), but cortisol insufficiency has not been documented. However, patients with FRM often experience worsening or demise following stress associated with infections. We investigated 2 female patients with FRM carrying the potentially novel homozygous FDXR mutation p.G437R with ambiguous genitalia at birth and sudden death in the first year of life; they presented with cortisol deficiency and androgen excess compatible with 11-hydroxylase deficiency. In addition, steroidogenic FDXR-variant cell lines reprogrammed from 3 patients with FRM fibroblasts displayed deficient mineralocorticoid and glucocorticoid production. Finally, Fdxr-mutant mice allelic to the severe p.R386W human variant showed reduced progesterone and corticosterone production. Therefore, our comprehensive studies show that human FDXR variants may cause compensated but possibly life-threatening adrenocortical insufficiency in stress by affecting adrenal glucocorticoid and mineralocorticoid synthesis through direct enzyme inhibition, most likely in combination with disturbed mitochondrial redox balance.

Dual-release hydrocortisone improves body composition and the glucometabolic profile in patients with secondary adrenal insufficiency.

PURPOSE: Studies have suggested improved metabolic profiles in patients with adrenal insufficiency treated with dual-release hydrocortisone (DR-HC) compared with conventional hydrocortisone (C-HC). This study investigates the effect of DR-HC compared with C-HC treatment on five health variables: diurnal salivary cortisol/cortisone, body composition, bone health, glucose metabolism, lipids, and blood pressure. METHODS: Prospective study of 27 participants (24 men) with secondary adrenal insufficiency with measurements during stable C-HC and 16 weeks after treatment switch to DR-HC. OUTCOMES: Diurnal salivary-cortisol/cortisone, body composition assessed by Dual-Energy X-ray absorptiometry scan, bone status indices (serum type I N-terminal procollagen [PINP], collagen type I cross-linked C-telopeptide [CTX], osteocalcin, receptor activator kappa-B [RANK] ligand, osteoprotegerin, and sclerostin), lipids, haemoglobin A1c (HbA1c), and 24-hour blood pressure. RESULTS: After the switch to DR-HC, the diurnal salivary-cortisol area under the curve (AUC) decreased non-significantly (mean difference: -55.9 nmol/L/day, P = 0.06). The salivary-cortisone-AUC was unchanged. Late-evening salivary-cortisol and cortisone were lower (-1.6 and -1.7 nmol/L, P = 0.002 and 0.004). Total and abdominal fat mass (-1.5 and -0.5 kg, P = 0.003 and 0.02), HbA1c (-1.2 mmol/mol, P = 0.02), and osteocalcin decreased (-7.0 µg/L, P = 0.03) whereas sclerostin increased (+41.1 pg/mL, P = 0.0001). The remaining bone status indices, lipids, and blood pressure were unchanged. CONCLUSION: This study suggests that switching to DR-HC leads to lower late-evening cortisol/cortisone exposure and a more favourable metabolic profile and body composition. In contrast, decreased osteocalcin with increasing sclerostin might indicate a negative impact on bones. CLINICAL TRIAL REGISTRATION: EudraCT201400203932.

Serum and salivary cortisol in the diagnosis of adrenal insufficiency and as a predictor of the outcome in patients with severe sepsis / Avaliação do cortisol sérico e salivar no diagnóstico da insuficiência adrenal e como parâmetro preditor da evolução de pacientes com sepse grave

OBJECTIVES: To compare salivary with serum total cortisol in patients with severe sepsis, postoperative patients and healthy controls. MATERIALS AND METHODS: Serum total cortisol was determined by chemiluminescence immunoassay; salivary cortisol was determined by enzyme immunoassay. RESULTS: In patients with severe sepsis, median concentration of salivary cortisol was 14.0 and 2.6 higher than that of postoperative patients and healthy subjects. In postoperative patients, salivary cortisol was 5.4 times higher than in control patients. Serum total cortisol was also higher in patients with severe sepsis than in controls and postoperative patients. This increment, however, was much lower (2.33 and 1.64, respectively). Patients with a salivary cortisol greater than 7.2 µg/dL had a mortality rate of 80 percent, a statistically significant result when compared with the group with lower cortisol levels (Z = 2.38 and p < 0.05). CONCLUSIONS: Salivary cortisol in critically ill patients may be a better laboratory indicator of cortisol levels than serum total cortisol.

OBJETIVOS: Comparar cortisol salivar com sérico total em pacientes com sepse grave, em pós-operatório e controles normais. MATERIAIS E MÉTODOS: Cortisol sérico total foi determinado por imunoensaio quimioluminescente e cortisol salivar por imunoensaio enzimático. RESULTADOS: Em pacientes com sepse grave, a mediana do cortisol salivar foi 14,0 e 2,6 vezes maior que dos pacientes em pós-operatório e saudáveis. Nos pacientes em pós-operatório, cortisol salivar foi 5,4 vezes maior que o controle. Cortisol sérico total também foi maior em pacientes com sepse grave que nos saudáveis e pós-operatórios, porém, esse incremento foi bem menor (2,33 e 1,64, respectivamente). Pacientes com cortisol salivar superior a 7,2 µg/dL tiveram mortalidade de 80 por cento, com significância estatística, quando comparado com os pacientes com níveis mais baixos (Z = 2,38 e p < 0,05). CONCLUSÕES: Cortisol salivar em pacientes críticos parece ser um melhor marcador da atividade glicocorticoide que o cortisol sérico total.