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Clarke SA, Eng PC, Comninos AN, Lazarus K, Choudhury S, Tsang C, Meeran K, Tan TM, Dhillo WS, Abbara A. Current Challenges and Future Directions in the Assessment of Glucocorticoid Status. Endocr Rev 2024; 45:795-817. [PMID: 38795365 PMCID: PMC11581704 DOI: 10.1210/endrev/bnae016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 05/07/2024] [Accepted: 05/23/2024] [Indexed: 05/27/2024]
Abstract
Glucocorticoid (GC) hormones are secreted in a circadian and ultradian rhythm and play a critical role in maintaining physiological homeostasis, with both excess and insufficient GC associated with adverse effects on health. Current assessment of GC status is primarily clinical, often in conjunction with serum cortisol values, which may be stimulated or suppressed depending on the GC disturbance being assessed. In the setting of extreme perturbations in cortisol levels ie, markedly low or high levels, symptoms and signs of GC dysfunction may be overt. However, when disturbances in cortisol GC status values are less extreme, such as when assessing optimization of a GC replacement regimen, signs and symptoms can be more subtle or nonspecific. Current tools for assessing GC status are best suited to identifying profound disturbances but may lack sensitivity for confirming optimal GC status. Moreover, single cortisol values do not necessarily reflect an individual's GC status, as they are subject to inter- and intraindividual variation and do not take into account the pulsatile nature of cortisol secretion, variation in binding proteins, or local tissue concentrations as dictated by 11beta-hydroxysteroid dehydrogenase activity, as well as GC receptor sensitivity. In the present review, we evaluate possible alternative methods for the assessment of GC status that do not solely rely on the measurement of circulating cortisol levels. We discuss the potential of changes in metabolomic profiles, micro RNA, gene expression, and epigenetic and other novel biomarkers such as growth differentiating factor 15 and osteocalcin, which could in the future aid in the objective classification of GC status.
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Affiliation(s)
- Sophie A Clarke
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Pei Chia Eng
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
- Department of Endocrinology, National University of Singapore, Singapore
| | - Alexander N Comninos
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Katharine Lazarus
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Sirazum Choudhury
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Christie Tsang
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
| | - Karim Meeran
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Tricia M Tan
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Waljit S Dhillo
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Ali Abbara
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
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Kalafateli M, Aggeletopoulou I, Triantos C. Adrenal insufficiency in liver diseases - pathophysiology and underlying mechanisms. Rev Endocr Metab Disord 2024; 25:663-676. [PMID: 38305832 DOI: 10.1007/s11154-024-09874-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/09/2024] [Indexed: 02/03/2024]
Abstract
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.
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Affiliation(s)
- Maria Kalafateli
- Department of Gastroenterology, General Hospital of Patras, 26332, Patras, Greece
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504, Patras, Greece
- Laboratory of Immunohematology, Department of Internal Medicine, Medical School, University of Patras, 26504, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504, Patras, Greece.
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Karthik V, Jabbar PK, Krishnadas D, Nair A, George GS, Jayakumari C, Soumya S, Asok A, Basheer S. Long-acting porcine ACTH stimulated salivary cortisol reduces the overdiagnosis of adrenal insufficiency compared to serum cortisol in cirrhosis liver. Clin Endocrinol (Oxf) 2024; 100:421-430. [PMID: 38368601 DOI: 10.1111/cen.15030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 01/02/2024] [Accepted: 01/30/2024] [Indexed: 02/20/2024]
Abstract
BACKGROUND There are no reliable methods in clinical practice to diagnose adrenal insufficiency (AI) in patients with cirrhosis owing to variable cortisol-binding protein levels. This leads to unreliable results in ACTH stimulated serum cortisol test. We aimed to estimate the long-acting porcine (LA)ACTH-stimulated serum and salivary cortisol levels of patients at different stages of cirrhosis using second generation electrochemiluminescence and to determine the prevalence of true adrenal insufficiency in these patients. DESIGN, PATIENTS AND MEASUREMENTS We included 135 noncritical patients with cirrhosis (45 each from CHILD A, B and C) and 45 healthy controls. Serum and salivary samples were collected at baseline in the morning and at 1 and 2 h after LA-ACTH injection. RESULTS In healthy subjects, the 2.5th centile of 2 h ACTH stimulated serum and salivary cortisol were 19.8 and 0.97 μg/dL, which were used as cut-offs for defining AI based on serum and saliva respectively. The median (interquartile-range) 2-h stimulated salivary cortisol in Child A, B, C categories and controls were 1.36(1.23-2.38), 1.46(1.18-2.22), 1.72(1.2-2.2) and 2.12(1.42-2.72) μg/dL respectively. Six subjects (4.4%) were diagnosed to have AI based on stimulated salivary cortisol cut-off, whereas 39 (28.9%) cirrhosis subjects had inadequately stimulated serum cortisol. Three patients (symptomatic) required steroid replacement therapy. Hypoalbuminemia was identified as a major risk factor for the misdiagnosis of adrenal insufficiency by serum cortisol-based testing. CONCLUSIONS Long-acting porcine ACTH stimulated salivary cortisol reduces the overdiagnosis of adrenal insufficiency compared to serum cortisol in cirrhosis liver. Stimulated salivary cortisol is a promising investigation for evaluation of adrenal function in cirrhosis and more studies are required for its further validation before clinical use.
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Affiliation(s)
- Vijayakumar Karthik
- Department of Endocrinology, Government Medical College Thiruvananthapuram, Thiruvananthapuram, India
| | | | - Devadas Krishnadas
- Department of Gastroenterology, Government Medical College Thiruvananthapuram, Thiruvananthapuram, India
| | - Abilash Nair
- Department of Endocrinology, Government Medical College Thiruvananthapuram, Thiruvananthapuram, India
| | | | - Chellamma Jayakumari
- Department of Endocrinology, Government Medical College Thiruvananthapuram, Thiruvananthapuram, India
| | - Sarayu Soumya
- Department of Endocrinology, Government Medical College Thiruvananthapuram, Thiruvananthapuram, India
| | - Arsha Asok
- Department of Endocrinology, Government Medical College Thiruvananthapuram, Thiruvananthapuram, India
| | - Shameer Basheer
- Department of Endocrinology, Government Medical College Thiruvananthapuram, Thiruvananthapuram, India
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Wentworth BJ, Schliep M, Novicoff W, Henry ZH, Siragy HM. Basal cortisol levels do not predict adrenal responsiveness in acute decompensated cirrhosis. Eur J Gastroenterol Hepatol 2024; 36:238-244. [PMID: 38131427 PMCID: PMC10752291 DOI: 10.1097/meg.0000000000002694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
OBJECTIVE Morning total cortisol (TC) levels have been shown to predict adrenal dysfunction (AD) in the general population, but their utility in cirrhosis is unknown. METHODS A retrospective cohort study was performed including all noncritically ill patients at our institution between 2011 and 2022 admitted with acute decompensated cirrhosis who underwent standard-dose adrenocorticotropic hormone (ACTH) stimulation testing. Adrenal dysfunction was defined as an increase in TC (delta TC) level <9 µg/dl 60 minutes after ACTH dosing. Spearman correlation was utilized to assess the relationship between binding globulins and cortisol levels. Multivariate regression analysis was performed to determine if basal TC level or common clinical parameters were predictive of AD. RESULTS One hundred and nineteen patients were included, with a median model for end-stage liver disease score of 18. Albumin levels did not correlate with basal TC levels (ρ = 0.127; P = 0.169); basal TC did not correlate with delta TC (ρ = 0.050; P = 0.591). The degree of hypoalbuminemia did not alter these relationships. On multivariate regression, only albumin level [odds ratio (OR) = 0.418; 95% confidence interval (CI), 0.196-0.890; P = 0.024] and MELD score (OR, 1.094; 95% CI, 1.019-1.174; P = 0.014) were predictive of AD. Basal TC levels were not predictive of AD (OR = 0.991; 95% CI, 0.903-1.088; P = 0.855) or delta TC (β = 0.000; 95% CI -0.147 to 0.147; P = 0.999). CONCLUSION Baseline TC levels do not predict ACTH stimulation testing response in patients with acute decompensated cirrhosis. Clinicians should avoid utilizing an isolated morning cortisol result as a screening method for AD in this population.
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Affiliation(s)
- Brian J Wentworth
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, VA
| | - Matthew Schliep
- Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA
| | - Wendy Novicoff
- Departments of Public Health Sciences and Orthopaedic Surgery, School of Medicine, University of Virginia Charlottesville, VA
| | - Zachary H Henry
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, VA
| | - Helmy M Siragy
- Division of Endocrinology & Metabolism, School of Medicine, University of Virginia, Charlottesville, VA
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Aggeletopoulou I, Tsounis EP, Kalafateli M, Michailidou M, Tsami M, Zisimopoulos K, Mandellou M, Diamantopoulou G, Kouskoura M, Michalaki M, Markopoulou CK, Thomopoulos K, Triantos C. Low Urinary Free Cortisol as a Risk Factor for Patients with Variceal Bleeding. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:2112. [PMID: 38138215 PMCID: PMC10744924 DOI: 10.3390/medicina59122112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 12/24/2023]
Abstract
Background and Objectives: Specificity and reliability issues of the current cortisol assessment methods lead to limitations on the accurate assessment of relative adrenal insufficiency. Although free cortisol provides a more accurate evaluation of adrenal cortisol production, the expense and time-consuming nature of these assays make them impractical for routine use. Research has, thus, focused on alternative methods, such as indirectly measuring free cortisol using Coolens' equation or directly assessing salivary cortisol concentration, which is considered a more favorable approach despite associated challenges like sampling issues and infection risks. The aim of this study was to explore correlations between 24 h urinary free cortisol (UFC), free plasma cortisol, serum total cortisol, and salivary cortisol as potential reliable indices of free cortisol in the setting of variceal bleeding. Additionally, we assessed the predictive value of UFC for 6-week mortality and 5-day treatment failure in patients with liver cirrhosis and variceal bleeding. Materials and Methods: A total of 40 outpatients with liver cirrhosis and variceal bleeding were enrolled. Free cortisol levels in serum, saliva, and urine were assessed using the electrochemiluminescence immunoassay method. For the measurement of plasma-free cortisol, a single quadrupole mass spectrometer was employed. The quantification of free cortisol was fulfilled by analyzing the signal response in the negative ESI-MS mode. Results: UFC was significantly correlated to free plasma cortisol. Negative correlations were demonstrated between UFC, the Child-Pugh (CP) score, and C reactive protein (CRP) levels. In the multivariate analysis, CP stage C was associated with 6-week mortality risk and portal vein thrombosis with 5-day treatment failure using Cox regression and binary logistic regression analyses, respectively. Patients who experienced rebleeding, infection, or death (or any combination of these events) presented with lower levels of UFC. Conclusions: This study suggests that low levels of UFC may impose a risk factor for patients with liver cirrhosis and variceal bleeding. The use of UFC as an index of adrenal cortisol production in variceal bleeding warrants further investigation.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.); (M.K.); (M.M.); (K.Z.); (G.D.); (K.T.)
| | - Efthymios P. Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.); (M.K.); (M.M.); (K.Z.); (G.D.); (K.T.)
| | - Maria Kalafateli
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.); (M.K.); (M.M.); (K.Z.); (G.D.); (K.T.)
| | - Maria Michailidou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.); (M.K.); (M.M.); (K.Z.); (G.D.); (K.T.)
| | - Maria Tsami
- Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Technology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (M.T.); (M.K.); (C.K.M.)
| | - Konstantinos Zisimopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.); (M.K.); (M.M.); (K.Z.); (G.D.); (K.T.)
| | - Martha Mandellou
- Department of Biochemistry, University Hospital of Patras, 26504 Patras, Greece;
| | - Georgia Diamantopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.); (M.K.); (M.M.); (K.Z.); (G.D.); (K.T.)
| | - Maria Kouskoura
- Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Technology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (M.T.); (M.K.); (C.K.M.)
| | - Marina Michalaki
- Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Internal Medicine, University of Patras, 26504 Patras, Greece;
| | - Catherine K. Markopoulou
- Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Technology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (M.T.); (M.K.); (C.K.M.)
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.); (M.K.); (M.M.); (K.Z.); (G.D.); (K.T.)
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.); (M.K.); (M.M.); (K.Z.); (G.D.); (K.T.)
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Ekawaravong S, Treepongkaruna S, Poomthavorn P, Pongratanakul S, Khlairit P, Chanprasertyothin S, Mahachoklertwattana P. Overdiagnosis of adrenal insufficiency in children with biliary atresia. Clin Pediatr Endocrinol 2023; 32:147-154. [PMID: 37362167 PMCID: PMC10288293 DOI: 10.1297/cpe.2022-0083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 04/03/2023] [Indexed: 06/28/2023] Open
Abstract
Serum cortisol mainly binds to the cortisol-binding globulin (CBG). Children with biliary atresia (BA) may have low serum CBG levels; thus, low serum total cortisol (TC) levels and adrenal insufficiency (AI) may be overdiagnosed. This study aimed to assess adrenal function in children with BA. All the patients underwent adrenocorticotropic hormone (ACTH) stimulation tests. Plasma ACTH, serum TC, and CBG levels were measured at baseline, with additional TC measurements at 30 and 60 min during testing. Free cortisol (FC) index (FCI) and calculated FC (cFC) were also calculated. AI was defined as peak TC <500 nmol/L (<18 μg/dL), peak FCI <12 nmol/mg, or peak cFC <33 nmol/L (<1.2 μg/dL). This study enrolled 71 children with BA. The Median (IQR) age of the patients was 5.5 (1.7-11.4) years. Twenty-five (35%) patients were diagnosed with AI based on the peak TC. In the AI group, the median serum CBG level was significantly lower than that in the non-AI group (481 vs. 533 nmol/L, p = 0.03). Only eight patients (11%) met all three AI criteria (six secondary AI and two primary AI). In conclusion, low serum CBG levels contribute to reduced peak TC and, consequently, overdiagnosing AI. Peak FCI and cFC could help reduce the overdiagnosis of AI.
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Affiliation(s)
- Suparat Ekawaravong
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Suporn Treepongkaruna
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Preamrudee Poomthavorn
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sarunyu Pongratanakul
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Patcharin Khlairit
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Pat Mahachoklertwattana
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Tan SYT, Tan HC, Zhu L, Loh LM, Lim DST, Swee DS, Chan YL, Lim HB, Ling SL, Ou EJ, Teo WE, Zhang XP, Goh HF, Kek PC. Expanding the use of salivary cortisol as a non-invasive outpatient test in the dynamic evaluation of suspected adrenal insufficiency. Endocr Connect 2023; 12:e230004. [PMID: 36799247 PMCID: PMC10083658 DOI: 10.1530/ec-23-0004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 02/16/2023] [Indexed: 02/18/2023]
Abstract
Background Adrenal insufficiency (AI) is potentially life-threatening, and accurate diagnosis is crucial. The first-line diagnostic test, the adrenocorticotrophic hormone (ACTH) stimulation test, measures serum total cortisol. However, this is affected in states of altered albumin or cortisol-binding globulin levels, limiting reliability. Salivary cortisol reflects free bioactive cortisol levels and is a promising alternative. However, few studies are available, and heterogenous methodologies limit applicability. Methods This study prospectively recruited 42 outpatients undergoing evaluation for AI, excluding participants with altered cortisol-binding states. Serum (immunoassay) and salivary (liquid chromatography tandem mass spectrometry) cortisol levels were sampled at baseline, 30 min, and 60 min following 250 µg synacthen administration. AI was defined as a peak serum cortisol level <500 nmol/L in accordance with guidelines. Results The study recruited 21 (50%) participants with AI and 21 without AI. There were no significant differences in baseline characteristics, blood pressure, or sodium levels between groups. Following synacthen stimulation, serum and salivary cortisol levels showed good correlation at all timepoints (R2 = 0.74, P < 0.001), at peak levels (R2 = 0.72, P < 0.001), and at 60 min (R2 = 0.72, P < 0.001). A salivary cortisol cut-off of 16.0 nmol/L had a sensitivity of 90.5% and a specificity of 76.2% for the diagnosis of AI. Conclusion This study demonstrates a good correlation between serum and salivary cortisol levels during the 250 µg synacthen test. A peak salivary cortisol cut-off of 16.0 nmol/L can be used for the diagnosis of AI. It is a less invasive alternative to evaluate patients with suspected AI. Its potential utility in the diagnosis of AI in patients with altered cortisol-binding states should be further studied.
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Affiliation(s)
| | - Hong Chang Tan
- Department of Endocrinology, Singapore General Hospital, Singapore
| | - Ling Zhu
- Department of Endocrinology, Singapore General Hospital, Singapore
| | - Lih Ming Loh
- Department of Endocrinology, Singapore General Hospital, Singapore
| | | | - Du Soon Swee
- Department of Endocrinology, Singapore General Hospital, Singapore
| | - Yoke Ling Chan
- Department of Speciality Nursing, Singapore General Hospital, Singapore
| | - Huee Boon Lim
- Department of Speciality Nursing, Singapore General Hospital, Singapore
| | - Shiau Lee Ling
- Department of Speciality Nursing, Singapore General Hospital, Singapore
| | - En Jun Ou
- Department of Speciality Nursing, Singapore General Hospital, Singapore
| | - Wynn Ee Teo
- Department of Speciality Nursing, Singapore General Hospital, Singapore
| | - Xiao Ping Zhang
- Department of Speciality Nursing, Singapore General Hospital, Singapore
| | - Hui Fen Goh
- Department of Speciality Nursing, Singapore General Hospital, Singapore
| | - Peng Chin Kek
- Department of Endocrinology, Singapore General Hospital, Singapore
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Wentworth BJ, Schliep M, Novicoff W, Siragy HM, Geng CX, Henry ZH. Relative adrenal insufficiency in the non-critically ill patient with cirrhosis: A systematic review and meta-analysis. Liver Int 2023; 43:660-672. [PMID: 36354293 PMCID: PMC9974795 DOI: 10.1111/liv.15473] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/05/2022] [Accepted: 11/08/2022] [Indexed: 11/12/2022]
Abstract
BACKGROUND & AIMS Characterization of relative adrenal insufficiency (RAI) in cirrhosis is heterogeneous with regard to studied patient populations and diagnostic methodology. We aimed to describe the prevalence and prognostic importance of RAI in non-critically ill patients with cirrhosis. METHODS A systematic review and meta-analysis was performed using MeSH terms and Boolean operators to search five large databases (Ovid-MEDLINE, ScienceDirect, Web of Science, Cochrane Library and ClinicalTrials.gov). The population of interest was patients with cirrhosis and without critical illness. The primary outcome was the pooled prevalence of RAI as defined by a peak total cortisol level <18 μg/dl, delta total cortisol <9 μg/dl or composite of the two thresholds in response either a standard-dose or low-dose short synacthen test. Odds ratios and standardized mean differences from random-effects models estimated important clinical outcomes and patient characteristics by adrenal functional status. RESULTS Twenty-two studies were included in final analysis, comprising 1991 patients with cirrhosis. The pooled prevalence of RAI was 37% (95% CI 33-42%). The prevalence of RAI varied by Child-Pugh classification, type of stimulation test used, specific diagnostic threshold and by severity of illness. Ninety-day mortality was significantly higher in patients with RAI (OR 2.88, 95% CI 1.69-4.92, I2 = 15%, p < 0.001). CONCLUSIONS Relative adrenal insufficiency is highly prevalent in non-critically ill patients with cirrhosis and associated with increased mortality. Despite the proposed multifactorial pathogenesis, no studies to date have investigated therapeutic interventions in this specific population.
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Affiliation(s)
- Brian J Wentworth
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, VA
| | - Matthew Schliep
- Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA
| | - Wendy Novicoff
- Departments of Public Health Sciences and Orthopaedic Surgery, School of Medicine, University of Virginia Charlottesville, VA
| | - Helmy M Siragy
- Division of Endocrinology & Metabolism, School of Medicine, University of Virginia, Charlottesville, VA
| | - Calvin X Geng
- Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA
| | - Zachary H Henry
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, VA
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9
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Wentworth BJ, Schliep M, Siragy HM, Henry ZH. Author's reply: Plasma corticosteroid-binding globulin levels in cirrhosis. Liver Int 2023; 43:742-743. [PMID: 36655408 DOI: 10.1111/liv.15525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023]
Affiliation(s)
- Brian J Wentworth
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Matthew Schliep
- Department of Medicine, School of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Helmy M Siragy
- Division of Endocrinology & Metabolism, School of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Zachary H Henry
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, Virginia, USA
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10
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Wentworth BJ, Henry ZH, Siragy HM. How I Approach It: Adrenal Insufficiency in Cirrhosis. Am J Gastroenterol 2022; 117:1889-1893. [PMID: 35980083 PMCID: PMC9722576 DOI: 10.14309/ajg.0000000000001939] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/29/2022] [Indexed: 01/30/2023]
Affiliation(s)
- Brian J Wentworth
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, VA
| | - Zachary H Henry
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, VA
| | - Helmy M Siragy
- Division of Endocrinology & Metabolism, School of Medicine, University of Virginia, Charlottesville, VA
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Adrenal histological and functional changes after hepatic encephalopathy: From mice model to an integrative bioinformatics analysis. Acta Histochem 2022; 124:151960. [PMID: 36202047 DOI: 10.1016/j.acthis.2022.151960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 09/28/2022] [Indexed: 11/15/2022]
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Abstract
Hypothalamus-pituitary-adrenal axis assessment in patients with cirrhosis is challenging. The phenotype of fatigue, hypotension, electrolyte disarray, and abdominal pain characterizing primary adrenal insufficiency (AI) overlaps significantly with decompensated liver disease. Reliance on total cortisol assays in hypoproteinemic states is problematic, yet abnormal stimulated levels in cirrhosis are associated with poor clinical outcomes. Alternative measures including free plasma or salivary cortisol levels have theoretical merit but are limited by unclear prognostic significance and undefined cirrhosis-specific reference ranges. Further complicating matters is that AI in cirrhosis represents a spectrum of impairment. Although absolute cortisol deficiency can occur, this represents a minority of cases. Instead, there is an emerging concept that cirrhosis, with or without critical illness, may induce a “relative” cortisol deficiency during times of stress. In addition, the limitations posed by decreased synthesis of binding globulins in cirrhosis necessitate re-evaluation of traditional AI diagnostic thresholds.
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Affiliation(s)
- Brian J Wentworth
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia , Charlottesville, VA
| | - Helmy M Siragy
- Division of Endocrinology & Metabolism, School of Medicine, University of Virginia , Charlottesville, VA
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13
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Kushnir MM, Nelson HA, Doyle K. Clinical Utility and Analytical Aspects of Direct Measurements of Free Hormones Using Mass Spectrometry-Based Methods. J Appl Lab Med 2022; 7:945-970. [PMID: 35296890 DOI: 10.1093/jalm/jfac010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/21/2022] [Indexed: 01/05/2025]
Abstract
BACKGROUND The free hormone (FH) hypothesis states that hormone action and the corresponding biological effects are mediated by the unbound (free) fraction of hormone in circulation. The in vivo relationship between protein-bound and FH is complex and dynamic. In most individuals, measurement of total hormone (TH) is usually adequate to reflect the hormone status; however, certain physiological conditions and/or medications can affect protein binding and alter FH concentration. In these cases, measurement of FH will provide a better measure of the bioactive hormone status than measurement of the TH. Measurement of FH presents many challenges, as the concentrations are very low and there are number of pitfalls, which may affect the measured concentrations. CONTENT In this review, we discuss techniques used in the separation and direct quantitation of FH concentrations in biological samples using mass spectrometry for analysis. We also highlight clinical situations in which FH analysis is warranted and when mass spectrometry should be the preferred methodology over immunoassays. SUMMARY Equilibrium dialysis, ultrafiltration, or size-exclusion separation coupled with liquid chromatography-tandem mass spectrometry provides a sensitive and specific method to measure FH concentrations. These direct methods are useful in iatrogenic or physiological states that alter hormone binding or metabolism.
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Affiliation(s)
- Mark M Kushnir
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT
- Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT
| | - Heather A Nelson
- Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT
| | - Kelly Doyle
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT
- Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT
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14
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Michailidou M, Aggeletopoulou I, Kouskoura M, Zisimopoulos K, Tsounis EP, Karaivazoglou K, Tourkochristou E, Mandellou M, Diamantopoulou G, Koutras N, Michalaki M, Gogos C, Velissaris D, Markopoulou CK, Thomopoulos K, Triantos C. Urinary free cortisol is a reliable index of adrenal cortisol production in patients with liver cirrhosis. Endocrine 2022; 76:697-708. [PMID: 35449323 DOI: 10.1007/s12020-022-03055-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 04/02/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND The measurement of total and free cortisol has been studied as a clinical index of adrenal cortisol production in patients with liver cirrhosis. Correlations between free plasma and salivary cortisol have previously been reported in stable cirrhotic patients. Urinary free cortisol constitutes an index of adrenal cortisol production; however, it has never been used in assessing adrenal function in patients with liver cirrhosis. AIMS The aim of this observational study was to determine associations between urinary free cortisol, serum total, salivary, measured and calculated plasma free cortisol levels in cirrhotics, determining which of them can be used as an indirect index of free cortisol levels. Moreover, we investigated the potential use of 24 h urinary free cortisol as a prognostic factor for mortality. METHODS Seventy-eight outpatients with liver cirrhosis were included. Serum, salivary and urinary free cortisol were measured using the electrochemiluminenscence immunoassay. Plasma free cortisol determination was conducted using a single quadrupole mass spectrometer. The quantification of free cortisol was achieved by determining the signal response on negative ESI-MS mode. RESULTS Twenty-four hour urinary free cortisol levels correlated with free cortisol determined by mass spectrometer, total cortisol and calculated free cortisol levels. Patients with low levels of urinary free cortisol presented a significantly higher mortality rate compared to those with high levels. The factors associated with death risk were determined by Cox regression. In the multivariate analysis, two models were applied; in the first model, CP score, PVT and urinary free cortisol were found to be significantly related to patients' survival, whereas in the second, MELD score, ascites and urinary free cortisol were independently related to survival. CONCLUSIONS This study suggests that 24 h urinary free cortisol could be considered as a potential index of adrenal cortisol production in patients with liver cirrhosis and it potentially detects patients with a high mortality risk.
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Affiliation(s)
- Maria Michailidou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Maria Kouskoura
- Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Technology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Zisimopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Katerina Karaivazoglou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Martha Mandellou
- Department of Biochemistry, University Hospital of Patras, Patras, Greece
| | - Georgia Diamantopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Nikolaos Koutras
- Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Technology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Marina Michalaki
- Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Internal Medicine, University of Patras, Patras, Greece
| | - Charalampos Gogos
- Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | | | - Catherine K Markopoulou
- Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Technology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece.
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15
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Assessment of adrenal response in patients with stable cirrhosis and ascites using different short Synacthen tests and definitions. Eur J Gastroenterol Hepatol 2021; 33:e540-e547. [PMID: 33905212 DOI: 10.1097/meg.0000000000002153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIMS The definition of relative adrenal insufficiency (RAI) in patients with cirrhosis remains controversial. We investigated the serum and salivary cortisol (SalC) response after low-dose and standard-dose Synacthen test in patients with stable cirrhosis and ascites. METHODS Ninety-five cirrhotic patients with ascites were prospectively evaluated from January 2014 to January 2018. Low-dose [adrenocorticotrophic hormone (ACTH): 1 μg] and standard-dose (ACTH: 250 μg) Synacthen test were successively performed. Paired serum total and saliva cortisol were taken at baseline, 30 min (low-dose test) and 60 min (standard-dose test). Salivary and Δserum total cortisol criteria included post-ACTH SalC < 12.7 ng/ml and/or SalC increase <3 ng/ml and serum total cortisol increase <9 μg/dl, respectively. RESULTS The prevalence of RAI varied according to the definition used. SalC-defined RAI was significantly more common after low-dose than standard-dose test (54.7% vs. 20%; P < 0.001). Δserum total cortisol-defined RAI was also significantly more frequent after low-dose than standard-dose test (66.3% vs. 24.2%; P < 0.001). Considering low-dose test/SalC criteria as reference diagnostic criteria, standard-dose/salivary and Δserum total cortisol criteria showed low specificity for RAI diagnosis (43.9% and 52.7%, respectively). Survival probability was significantly lower in patients with low-dose test/SalC-defined RAI compared to those without (53.8% vs. 79.1%; P = 0.01). SalC-defined RAI after low-dose test was significantly more common than that defined after standard-dose test (72.7% vs. 30.3%; P < 0.001) among patients who died. CONCLUSION Low-dose test/SalC definition can identify RAI in about half of patients with stable cirrhosis and ascites and is associated with increased mortality.
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16
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Siramolpiwat S, Kerdsuknirun J, Tharavanij T. An impact of relative adrenal insufficiency on short-term outcomes in non-critically ill cirrhotic patients: A prospective cohort study. Int J Clin Pract 2021; 75:e14362. [PMID: 33993598 DOI: 10.1111/ijcp.14362] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 05/09/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Relative adrenal insufficiency (RAI) is frequently found in patients with liver cirrhosis, especially in critically ill conditions. However, the prognostic impact of RAI in non-critically ill cirrhosis remains controversial. The aim of the present study was to assess the prevalence of RAI and its prognostic implication in non-critically ill cirrhotic patients. METHODS From December 2015 to November 2017, hospitalised non-critically ill cirrhotic patients admitted with hepatic decompensation were prospectively enrolled in this study. Within 24 hours after admission, 250 mcg ACTH stimulation test was performed. RAI was defined as an increase in serum cortisol <9 mcg/dL in patients with basal serum cortisol <35 mcg/dL. Clinical outcomes were evaluated during admission and at 30-, 90-day visits. RESULTS One hundred and fifteen patients were included (66% male, mean age 59.9 ± 16 years, mean MELD 16.1 ± 6.8, Child A/B/C 15.7%/53.9%/30.4%). The main indications for admission were bacterial infection (44.6%) and portal hypertension-related bleeding (19.1%). RAI was detected in 35 patients (30.4%). Patients with RAI had higher Child-Pugh score (9.4 ± 1.9 vs 8.0 ± 1.7, P < .01), and MELD scores (18.3 ± 5.9 vs 15.1 ± 6.9, P = .02). The in-hospital, 30-, and 90-day mortality rates were 9.6%, 20.9%, and 26.1%, respectively. There was no significant difference in the incidence of nosocomial infection, severe sepsis, septic shock, HRS, and mortality rates between patients with and without RAI. By multivariate analysis, bacterial infection on admission (HR 3.13, P < .01) and acute-on-chronic liver failure (HR 4.98, P < .001) were independent predictors of 90-day survival. CONCLUSIONS RAI is found in about one-third of hospitalised non-critically ill cirrhotic patients and is associated with the severity of cirrhosis. However, the presence of RAI has no influence on short-term outcomes.
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Affiliation(s)
- Sith Siramolpiwat
- Department of Medicine, Chulabhorn International College of Medicine (CICM), Thammasat University, Pathumthani, Thailand
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Jitrapa Kerdsuknirun
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Thipaporn Tharavanij
- Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
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Hung TH, Tseng CW, Tsai CC, Lee HF. Prognosis of hypoglycemia episode in cirrhotic patients during hospitalization. BMC Gastroenterol 2021; 21:319. [PMID: 34372791 PMCID: PMC8351368 DOI: 10.1186/s12876-021-01895-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 08/03/2021] [Indexed: 12/22/2022] Open
Abstract
Background Studies have shown that hyperglycemia in cirrhotic patients increases mortality. However, no population-based study has evaluated the influence of hypoglycemia upon hospital admission on death in these patients. The aim of this study was to assess the effect of hypoglycemia at admission on the mortality of patients with liver cirrhosis. Methods The Taiwan National Health Insurance Database was searched, and 636 cirrhotic patients without baseline diabetes mellitus who presented with hypoglycemia upon hospitalized from 2010 to 2013 were included in the study. A one-to-four propensity score matching was performed to select a comparison group based on age, sex and comorbidities. Results The overall 30-day mortality rate was 30.2% in the hypoglycemia group and 7.4% in the non-hypoglycemia group (P < 0.001). After Cox regression modeling adjusting for age, sex and comorbid disorders, cirrhotic patients with hypoglycemia had a hazard ratio (HR) of 30-day mortality of 4.96 (95% confidence interval [CI] 4.05–6.08, P < 0.001) as compared to the non-hypoglycemia group. In subgroup analysis, the cirrhotic patients with hypoglycemia and hepatocellular carcinoma (HCC) had a 30-day mortality HR of 6.11 (95% confidence interval [CI] 4.40–8.49, P < 0.001) compared to those with neither hypoglycemia nor HCC. Conclusions Hypoglycemia is a very important prognostic factor in the 30-day mortality of cirrhotic patients, especially in those with underlying HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-021-01895-2.
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Affiliation(s)
- Tsung-Hsing Hung
- Division of Gastroenterology, Department of Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 2, Minsheng Rd., Dalin Township, Chiayi County, 62247, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chih-Wei Tseng
- Division of Gastroenterology, Department of Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 2, Minsheng Rd., Dalin Township, Chiayi County, 62247, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chih-Chun Tsai
- Department of Mathematics, Tamkang University, Tamsui, Taiwan
| | - Hsing-Feng Lee
- Division of Gastroenterology, Department of Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 2, Minsheng Rd., Dalin Township, Chiayi County, 62247, Taiwan. .,School of Medicine, Tzu Chi University, Hualien, Taiwan.
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Wentworth BJ, Haug RM, Northup PG, Caldwell SH, Henry ZH. Abnormal cholesterol metabolism underlies relative adrenal insufficiency in decompensated cirrhosis. Liver Int 2021; 41:1913-1921. [PMID: 34028160 DOI: 10.1111/liv.14970] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 05/02/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022]
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. High-density 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, R2 = 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.
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Affiliation(s)
- Brian J Wentworth
- Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA, USA
| | - Rebecca M Haug
- Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA
| | - Patrick G Northup
- Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA, USA
| | - Stephen H Caldwell
- Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA, USA
| | - Zachary H Henry
- Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA, USA
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Zhang J, Li J, Chen Y, Ding M, Duan Z. Prognostic Factors Related to the Mortality Rate of Acute-on-Chronic Liver Failure Patients. Diabetes Metab Syndr Obes 2021; 14:2573-2580. [PMID: 34135609 PMCID: PMC8200164 DOI: 10.2147/dmso.s309641] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/21/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Critical illness-related corticosteroid insufficiency (CIRCI) is known to be a common complication in patients with acute-on-chronic liver failure (ACLF). However, factors that predict the survival rate of ACLF patients remain unclear. The present study aims to determine the prognostic factors that impinge on the survival rate of ACLF patients. METHODS A total of 90 patients with ACLF at different stages, with or without CIRCI, were prospectively evaluated. RESULTS Various clinical factors were found to be significantly different among patients at early, mid and late stages of ACLF, as well as between the same population of patients with and without CIRCI. Specifically, patients at later stages of ACLF and patients with CIRCI had significantly higher Child-Turcotte-Pugh (CTP), Model for End-Stage Liver Disease (MELD) and ACLF Research Consortium (AARC)-ACLF scores. CIRCI was observed in 20% of the enrolled patients (18 out of 90). In addition, the 90-day mortality rate was higher in mid- and late-stage ACLF patients, as well as patients with CIRCI. CONCLUSION ACLF stage and CIRCI predict early mortality in patients with ACLF and could be actively monitored in these patients for prioritized liver transplantation.
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Affiliation(s)
- Jian Zhang
- Difficult & Complicated Liver diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, People’s Republic of China
| | - Junfeng Li
- The First Hospital of Lanzhou University, Department of Infectious Diseases, Lanzhou, People’s Republic of China
| | - Yu Chen
- Difficult & Complicated Liver diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, People’s Republic of China
| | - Mei Ding
- Difficult & Complicated Liver diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, People’s Republic of China
| | - Zhongping Duan
- Difficult & Complicated Liver diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, People’s Republic of China
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Swales H, Batchelor DJ, O'Connell EM. Evaluation of serum cortisol concentration as a prognostic indicator for nonsurvival to hospital discharge in critically ill dogs. J Am Vet Med Assoc 2020; 256:1034-1040. [PMID: 32301661 DOI: 10.2460/javma.256.9.1034] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To investigate whether serum cortisol (SC) concentration is a useful prognostic indicator for survival versus nonsurvival to hospital discharge in critically ill dogs. ANIMALS 229 client-owned dogs. PROCEDURES Medical records were retrospectively reviewed to identify critically ill dogs that were hospitalized between January 2010 and May 2018 and that had SC concentrations measured ≤ 3 days after admission. Results for SC concentrations were compared for dogs grouped by survival versus nonsurvival to hospital discharge, with versus without sepsis, and other variables of interest. The predictive value of SC concentration for nonsurvival to hospital discharge was assessed (OR, sensitivity, and specificity) for cutoffs determined from a ROC curve or reference limit. RESULTS Median SC concentration was higher in dogs that did not survive to hospital discharge (8.5 μg/dL; interquartile [25th to 75th percentile] range, 4.8 to 11.8 μg/dL), compared with concentration in those that were discharged alive (4.5 μg/dL; interquartile range, 2.5 to 6.9 μg/dL). The area under the ROC curve was 0.72 (95% confidence interval [CI], 0.64 to 0.81) for SC concentration predicting nonsurvival. The calculated optimum cutoff of SC concentration was 7.6 μg/dL, at which the OR, sensitivity, and specificity for nonsurvival were 5.4 (95% CI, 2.7 to 10.9), 58%, and 80%, respectively. Alternatively, when the upper reference limit for SC concentration (5.8 μg/dL) was used as the cutoff, the OR, sensitivity, and specificity for nonsurvival were 3.6 (95% CI, 1.8 to 7.1), 67%, and 64%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that SC concentration could be used as part of an overall assessment of prognosis in critically ill dogs.
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Piano S, Favaretto E, Tonon M, Antonelli G, Brocca A, Sticca A, Mareso S, Gringeri E, Scaroni C, Plebani M, Russo FP, Burra P, Cillo U, Angeli P. Including Relative Adrenal Insufficiency in Definition and Classification of Acute-on-Chronic Liver Failure. Clin Gastroenterol Hepatol 2020; 18:1188-1196.e3. [PMID: 31589973 DOI: 10.1016/j.cgh.2019.09.035] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 09/14/2019] [Accepted: 09/26/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Relative adrenal insufficiency (RAI) is defined by insufficient production of cortisol relative to organ demand. RAI is observed frequently in hospitalized patients with cirrhosis, but there is disagreement over the clinical effects of RAI in these patients. We evaluated the prevalence and the clinical effects of RAI in hospitalized patients with cirrhosis. METHODS We performed a prospective study of 160 patients admitted to a hospital in Italy for acute decompensation of cirrhosis from May 2011 through September 2016. Patients were followed up until death, liver transplantation, or a maximum of 90 days. Serum and salivary levels of cortisol were measured before and after a 1-hour Short Synacthen Test. A diagnosis of RAI was given to patients with an increase in serum cortisol of less than 9 μg/dL, after Synacthen administration, in patients with baseline serum levels of cortisol less than 35 μg/dL. We collected blood samples before the Synacthen test and analyzed them for blood cell counts, liver and renal function, levels of C-reactive protein, and lipid profiles (total cholesterol, high-density lipoprotein cholesterol, apolipoprotein-A1). RESULTS A diagnosis of RAI was made for 78 patients (49%). Age (odds ratio [OR], 0.95; P = .030), number of leukocytes (OR, 3.10; P = .006), and levels of high-density lipoprotein cholesterol (OR, 0.30; P = .039) were associated independently with RAI. Patients with RAI had a significantly higher risk of developing bacterial infections (hazard ratio [HR], 1.60; P = .038), sepsis (HR, 2.95; P = .001), septic shock (HR, 4.94; P = .038), new organ failures (HR, 2.45; P = .014), and acute-on-chronic liver failure (HR, 2.27; P = .037) than patients without RAI. RAI was associated independently with death within 90 days of diagnosis (subdistribution HR, 4.83; P = .001). Patients with RAI and mild renal dysfunction or hepatic encephalopathy had no significant difference in cumulative incidence of 28-day mortality vs patients with acute-on-chronic liver failure grade 1 (25% vs 22%). CONCLUSIONS We found RAI to occur in almost half of patients admitted to a hospital for acute decompensation of cirrhosis. RAI was associated with a deficit of substrates for steroidogenesis and an increase in markers of inflammation. Patients with RAI have a high risk of developing sepsis, septic shock, organ failure, and death within 90 days. RAI has similar prognostic value to nonrenal organ failures.
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Affiliation(s)
- Salvatore Piano
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Elisa Favaretto
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Marta Tonon
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Giorgia Antonelli
- Unit of Laboratory Medicine, Department of Medicine, University of Padova, Padova, Italy
| | - Alessandra Brocca
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Antonietta Sticca
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Sara Mareso
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Carla Scaroni
- Unit of Endocrinology, Department of Medicine, University of Padova, Padova, Italy
| | - Mario Plebani
- Unit of Laboratory Medicine, Department of Medicine, University of Padova, Padova, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy.
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Vieira-Correa M, Giorgi RB, Oliveira KC, Hayashi LF, Costa-Barbosa FA, Kater CE. Saliva versus serum cortisol to identify subclinical hypercortisolism in adrenal incidentalomas: simplicity versus accuracy. J Endocrinol Invest 2019; 42:1435-1442. [PMID: 31456173 DOI: 10.1007/s40618-019-01104-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 08/21/2019] [Indexed: 12/21/2022]
Abstract
PURPOSE Subclinical hypercortisolism (SCH) leads to metabolic derangements and increased cardiovascular risk. Cortisol autonomy is defined by the overnight 1 mg dexamethasone suppression test (DST). Saliva cortisol is an easier, stress-free, and cost-effective alternative to serum cortisol. We compared 23 h and post-1 mg DST saliva with serum cortisol to identify SCH in adrenal incidentalomas (AI). METHODS We analyzed 359 DST obtained retrospectively from 226 AI subjects (173F/53 M; 19-83 years) for saliva and serum cortisol. We used three post-DST serum cortisol cutoffs to uncover SCH: 1.8, 2.5, and 5.0 μg/dL. We determined post-DST and 23 h saliva cortisol cutoffs by ROC curve analysis and calculated their sensitivities (S) and specificities (E). RESULTS The sensitive 1.8 μg/dL cutoff defined 137 SCH and 180 non-functioning adenomas (NFA): post-DST and 23 h saliva cortisol S/E were: 75.2%/74.4% and 59.5%/65.9%, respectively. Using the specific 5.0 μg/dL cortisol cutoff (22 SCH/295 NFA), post-DST and 23 h saliva cortisol S/E were 86.4%/83.4% and 66.7%/80.4%, respectively. Using the intermediate 2.5 μg/dL cutoff (89 SCH/228 NFA), post-DST and 23 h saliva cortisol S/E were 80.9%/68.9% and 65.5%/62.8%, respectively. CONCLUSION Saliva cortisol showed acceptable performance only with the 5.0 μg/dL cortisol cutoff, as in overt Cushing's syndrome. Lower cutoffs (1.8 and 2.5 μg/dL) that identify larger samples of patients with poor metabolic outcomes are less accurate for screening. These results may be attributed to pre-analytical factors and inherent patient conditions. Thus, saliva cortisol cannot replace serum cortisol to identify SCH among patients with AI for screening DST.
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Affiliation(s)
- M Vieira-Correa
- From the Adrenal and Hypertension Unit, Division of Endocrinology and Metabolism, Department of Medicine, Federal University of São Paulo School of Medicine (Escola Paulista de Medicina/Universidade Federal de São Paulo), Rua Pedro de Toledo, 781-13th Floor, São Paulo, SP, 04039-032, Brazil
| | - R B Giorgi
- From the Adrenal and Hypertension Unit, Division of Endocrinology and Metabolism, Department of Medicine, Federal University of São Paulo School of Medicine (Escola Paulista de Medicina/Universidade Federal de São Paulo), Rua Pedro de Toledo, 781-13th Floor, São Paulo, SP, 04039-032, Brazil
| | - K C Oliveira
- From the Adrenal and Hypertension Unit, Division of Endocrinology and Metabolism, Department of Medicine, Federal University of São Paulo School of Medicine (Escola Paulista de Medicina/Universidade Federal de São Paulo), Rua Pedro de Toledo, 781-13th Floor, São Paulo, SP, 04039-032, Brazil
| | - L F Hayashi
- From the Adrenal and Hypertension Unit, Division of Endocrinology and Metabolism, Department of Medicine, Federal University of São Paulo School of Medicine (Escola Paulista de Medicina/Universidade Federal de São Paulo), Rua Pedro de Toledo, 781-13th Floor, São Paulo, SP, 04039-032, Brazil
| | - F A Costa-Barbosa
- From the Adrenal and Hypertension Unit, Division of Endocrinology and Metabolism, Department of Medicine, Federal University of São Paulo School of Medicine (Escola Paulista de Medicina/Universidade Federal de São Paulo), Rua Pedro de Toledo, 781-13th Floor, São Paulo, SP, 04039-032, Brazil
| | - C E Kater
- From the Adrenal and Hypertension Unit, Division of Endocrinology and Metabolism, Department of Medicine, Federal University of São Paulo School of Medicine (Escola Paulista de Medicina/Universidade Federal de São Paulo), Rua Pedro de Toledo, 781-13th Floor, São Paulo, SP, 04039-032, Brazil.
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Dichtel LE, Schorr M, Loures de Assis C, Rao EM, Sims JK, Corey KE, Kohli P, Sluss PM, McPhaul MJ, Miller KK. Plasma Free Cortisol in States of Normal and Altered Binding Globulins: Implications for Adrenal Insufficiency Diagnosis. J Clin Endocrinol Metab 2019; 104:4827-4836. [PMID: 31009049 PMCID: PMC6735741 DOI: 10.1210/jc.2019-00022] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/16/2019] [Indexed: 01/31/2023]
Abstract
CONTEXT Accurate diagnosis of adrenal insufficiency is critical because there are risks associated with overdiagnosis and underdiagnosis. Data using liquid chromatography tandem mass spectrometry (LC/MS/MS) free cortisol (FC) assays in states of high or low cortisol-binding globulin (CBG) levels, including cirrhosis, critical illness, and oral estrogen use, are needed. DESIGN Cross-sectional. OBJECTIVE Determine the relationship between CBG and albumin as well as total cortisol (TC) and FC in states of normal and abnormal CBG. Establish the FC level by LC/MS/MS that best predicts TC of <18 μg/dL (497 nmol/L) (standard adrenal insufficiency diagnostic cutoff) in healthy individuals. SUBJECTS This study included a total of 338 subjects in four groups: healthy control (HC) subjects (n = 243), patients with cirrhosis (n = 38), intensive care unit patients (ICU) (n = 26), and oral contraceptive (OCP) users (n = 31). MAIN OUTCOME MEASURE(S) FC and TC by LC/MS/MS, albumin by spectrophotometry, and CBG by ELISA. RESULTS TC correlated with FC in the ICU (R = 0.91), HC (R = 0.90), cirrhosis (R = 0.86), and OCP (R = 0.70) groups (all P < 0.0001). In receiver operator curve analysis in the HC group, FC of 0.9 μg/dL (24.8 nmol/L) predicted TC of <18 μg/dL (497 nmol/L; 98% sensitivity, 91% specificity; AUC, 0.98; P < 0.0001). Decreasing the cutoff to 0.7 μg/dL led to a small decrease in sensitivity (92%) with similar specificity (91%). CONCLUSIONS A cutoff FC of <0.9 μg/dL (25 nmol/L) in this LC/MS/MS assay predicts TC of <18 μg/dL (497 nmol/L) with excellent sensitivity and specificity. This FC cutoff may be helpful in ruling out adrenal insufficiency in patients with binding globulin derangements.
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Affiliation(s)
- Laura E Dichtel
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Correspondence and Reprint Requests: Laura E. Dichtel, MD, MHS, Neuroendocrine Unit, Massachusetts General Hospital, BUL457B, 55 Fruit Street, Boston, Massachusetts 02114. E-mail:
| | - Melanie Schorr
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | | | - Elizabeth M Rao
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Jessica K Sims
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Kathleen E Corey
- Harvard Medical School, Boston, Massachusetts
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Puja Kohli
- Harvard Medical School, Boston, Massachusetts
- Division of Pulmonology and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Patrick M Sluss
- Harvard Medical School, Boston, Massachusetts
- Clinical Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Michael J McPhaul
- Endocrinology, Quest Diagnostics Nichols Institute, San Juan Capistrano, California
| | - Karen K Miller
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
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Charni-Natan M, Aloni-Grinstein R, Osher E, Rotter V. Liver and Steroid Hormones-Can a Touch of p53 Make a Difference? Front Endocrinol (Lausanne) 2019; 10:374. [PMID: 31244779 PMCID: PMC6581675 DOI: 10.3389/fendo.2019.00374] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 05/28/2019] [Indexed: 12/12/2022] Open
Abstract
The liver is the main metabolic organ in the body, serving as a significant hormonal secretory gland and functioning to maintain hormone balance and homeostasis. Steroid hormones regulate various biological pathways, mainly in the reproductive system and in many metabolic processes. The liver, as well as steroid hormones, contribute significantly, through functional intertwine, to homeostasis maintenance, and proper responses during stress. Malfunction of either has a significant impact on the other and may lead to severe liver diseases as well as to several endocrine syndromes. Thus, the regulation on liver functions as on steroid hormones levels and activities is well-controlled. p53, the well-known tumor suppressor gene, was recently found to regulate metabolism and general homeostasis processes, particularly within the liver. Moreover, p53 was shown to be involved in steroid hormones regulation. In this review, we discuss the bi-directional regulation of the liver and the steroid hormones pointing to p53 as a novel regulator in this axis. A comprehensive understanding of the molecular mechanisms of this axis may help to prevent and treat related disease, especially with the increasing exposure of the population to environmental steroid hormones and steroid hormone-based medication.
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Affiliation(s)
- Meital Charni-Natan
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ronit Aloni-Grinstein
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
- Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel
| | - Etty Osher
- Sackler Faculty of Medicine, Tel Aviv-Sourasky Medical Center, Institute of Endocrinology Metabolism and Hypertension, Tel Aviv University, Tel Aviv, Israel
| | - Varda Rotter
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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25
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Theocharidou E, Giouleme O, Anastasiadis S, Markopoulou A, Pagourelias E, Vassiliadis T, Fotoglidis A, Agorastou P, Slavakis A, Balaska A, Kouskoura MG, Gossios TD, Karagiannis A, Mantzoros CS. Free Cortisol Is a More Accurate Marker for Adrenal Function and Does Not Correlate with Renal Function in Cirrhosis. Dig Dis Sci 2019; 64:1686-1694. [PMID: 30659471 DOI: 10.1007/s10620-019-5460-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 01/08/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND The accuracy of diagnosis and clinical implications of the hepatoadrenal syndrome, as currently diagnosed using total cortisol, remain to be validated. AIM The aim of this study was to assess adrenal function using free cortisol in stable cirrhosis and study the potential implications of any abnormalities for renal and/or cardiac function. METHODS Sixty-one stable consecutively enrolled patients with cirrhosis underwent assessment of adrenal function using the low-dose short Synacthen test, renal function by 51Cr-EDTA glomerular filtration rate (GFR), and cardiac function by two-dimensional echocardiography. RESULTS Eleven patients (18%) had total peak cortisol (PC) < 500 nmol/L, but no patient had free PC < 33 nmol/L indicating that diagnosis of AI using total cortisol is not confirmed using free cortisol. Free cortisol did not correlate with GFR or parameters of cardiac function. Patients with higher Child-Pugh class had progressively lower free cortisol. Patients with low GFR < 60 mL/min (N = 22) had more frequently grade II-III diastolic dysfunction (66.7% vs. 17.6%; p = 0.005) and had higher Child-Pugh and MELD score compared to those with normal GFR. CONCLUSIONS Diagnosis of AI using total cortisol is not confirmed using free cortisol and is thus considered unreliable in cirrhosis. Free cortisol is not associated with renal or cardiac dysfunction. Lower free cortisol in more advanced stages of liver disease might be secondary to decreased synthesis due to lower cholesterol levels. Irrespective of free cortisol, parameters of cardiac dysfunction are associated with renal impairment supporting the cardio-renal hypothesis.
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Affiliation(s)
| | - Olga Giouleme
- 2nd Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Sotirios Anastasiadis
- 2nd Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Aikaterini Markopoulou
- School of Pharmacy, Laboratory of Pharmaceutical Analysis, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Efstathios Pagourelias
- 3rd Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Themistoklis Vassiliadis
- 3rd Department of Internal Medicine, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Athanasios Fotoglidis
- 3rd Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Polyxeni Agorastou
- 2nd Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Aristeidis Slavakis
- Department of Biochemistry, Hippokration General Hospital, Thessaloníki, Greece
| | - Aikaterini Balaska
- Laboratory of the 2nd Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Maria G Kouskoura
- School of Pharmacy, Laboratory of Pharmaceutical Analysis, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Thomas D Gossios
- 2nd Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Asterios Karagiannis
- 2nd Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Christos S Mantzoros
- Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
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26
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Theiler-Schwetz V, Zaufel A, Schlager H, Obermayer-Pietsch B, Fickert P, Zollner G. Bile acids and glucocorticoid metabolism in health and disease. Biochim Biophys Acta Mol Basis Dis 2019; 1865:243-251. [DOI: 10.1016/j.bbadis.2018.08.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 07/18/2018] [Accepted: 08/01/2018] [Indexed: 12/12/2022]
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Kumar M, Gupta GK, Wanjari SJ, Tak V, Ameta M, Nijhawan S. Relative Adrenal Insufficiency in Patients with Alcoholic Hepatitis. J Clin Exp Hepatol 2019; 9:215-220. [PMID: 31024204 PMCID: PMC6477128 DOI: 10.1016/j.jceh.2018.09.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 09/04/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND/AIMS Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with high morbidity and mortality. Treatment with steroids is known to decrease short-term mortality in severe AH patients. Hence, we hypothesize that adrenal insufficiency can be associated with severe AH and affects prognosis. The aim of this study was (1) to evaluate relative adrenal insufficiency (RAI) in patients with AH and (2) to Compare RAI with the severity of AH. METHODS Newly diagnosed cases of AH hospitalized in SMS Medical College and Hospital, Department of Gastroenterology were, enrolled. All patients of AH were classified as mild and severe AH on the basis of Maddrey discriminant function (DF). After baseline serum cortisol, 25 IU ACTH (Adreno Corticotrophic Hormone) was injected intramuscularly and blood sample was collected after 1 h and assessed for serum cortisol. RAI was defined as <7 μg increase in the cortisol level from baseline. RAI was compared with severity of AH. RESULTS Of 120 patients of AH, 58 patients fulfilled the inclusion criteria, in which 48 patients were diagnosed as severe AH and 10 patients were diagnosed as mild AH. In patients with severe AH, the baseline mean serum cortisol level was significantly high as compared with mild AH; 26 patients (54.16 %) of 48 patients with severe AH showed RAI (P ≤ 0.001).Whereas in patients with mild AH, none of patients showed RAI. RAI also showed negative correlation with DF. There was no difference in RAI with respect to acute kidney injury (AKI). CONCLUSION RAI is a common entity in patients with severe AH, and it is related with the severity of disease.
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Key Words
- ACTH, Adreno Corticotrophic Hormone
- AH, Alcoholic Hepatitis
- AI, Adrenal Insuffiency
- AKI, Acute Kidney Injury
- ALD, Alcoholic Liver Disease
- ALT, Alanine Aminotranferase
- AST, Aspartate Aminotransferase
- CIRCI (Critical Illness Related Corticosteroid Insufficiency)
- CIRCI, Critical Illness Related Corticosteroid Insufficiency
- DF, Discriminant Function
- HPA, Hypothalamic Pituitary Adrenal
- INR, International Normalised Ratio
- MELD, Model for End-stage Liver Disease
- PT, Prothrombin Time
- RAI, Relative Adrenal Insuffiency
- TLC, Total Leucocyte Count
- alcoholic hepatitis
- relative adrenal insufficiency
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Affiliation(s)
| | - Gaurav K. Gupta
- Address for correspondence: Gaurav Kumar Gupta, MD, DM. Department of Gastroenterology, SMS Medical College & Hospital, Jaipur, India. Tel.: +91 9214027938.
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Singh RR, Walia R, Sachdeva N, Bhalla A, Singh A, Singh V. Relative adrenal insufficiency in cirrhotic patients with ascites (hepatoadrenal syndrome). Dig Liver Dis 2018; 50:1232-1237. [PMID: 29887344 DOI: 10.1016/j.dld.2018.05.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 04/11/2018] [Accepted: 05/12/2018] [Indexed: 02/08/2023]
Abstract
AIM Relative adrenal insufficiency (RAI) has been reported in critically ill patients with cirrhosis. We evaluated the prevalence of RAI and its relationship to clinical course in non-septic cirrhosis patients with ascites. METHODS The study included 66 consecutive non-septic cirrhosis patients with ascites. RAI was defined by a delta cortisol lower than 9 μg/dL and/or a peak cortisol lower than 18 μg/dL. RESULTS Sixty-six patients with cirrhosis and ascites were studied. The mean Child-Turcotte-Pugh (CTP) and model for end stage liver disease (MELD) scores were 10.6 ± 1.9 and 21.5 ± 7.3, respectively. The prevalence of RAI in patients with cirrhosis and ascites was 47% (31/66). The prevalence of RAI in patients with and without spontaneous bacterial peritonitis, renal failure and type 1 hepatorenal syndrome (HRS) was comparable. Baseline hyponatremia was common in RAI (42% versus 17%, p = 0.026). There was a significant correlation of prevalence of RAI with prothrombin time, international normalized ratio, MELD scores and CTP class. During follow-up, there was no association between RAI and the risk to develop new infections, severe sepsis, type 1 HRS and death. CONCLUSIONS RAI is common in non-septic cirrhotic patients with ascites and its prevalence increases with severity of liver disease. However, it does not affect the short-term outcome in these patients.
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Affiliation(s)
- Rajiv Ranjan Singh
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rama Walia
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Naresh Sachdeva
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashish Bhalla
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Akash Singh
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Virendra Singh
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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Angeli P, Bernardi M, Villanueva C, Francoz C, Mookerjee RP, Trebicka J, Krag A, Laleman W, Gines P. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018; 69:406-460. [PMID: 29653741 DOI: 10.1016/j.jhep.2018.03.024] [Citation(s) in RCA: 1775] [Impact Index Per Article: 253.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 03/28/2018] [Indexed: 02/06/2023]
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Park SH, Joo MS, Kim BH, Yoo HN, Kim SE, Kim JB, Jang MK, Kim DJ, Lee MS. Clinical characteristics and prevalence of adrenal insufficiency in hemodynamically stable patients with cirrhosis. Medicine (Baltimore) 2018; 97:e11046. [PMID: 29952944 PMCID: PMC6039635 DOI: 10.1097/md.0000000000011046] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Accepted: 05/13/2018] [Indexed: 01/15/2023] Open
Abstract
It is well known that adrenal insufficiency is common in septic shock or hemodynamically unstable patients. But, there is as yet no sufficient clinically significant data about the exact prevalence or differences in the cause of cirrhosis with adrenal insufficiency. To investigate adrenal insufficiency prevalence in hemodynamically stable patients with cirrhosis and determine differences based on cirrhosis severity or etiology.From July 2011 to December 2012, 69 hemodynamically stable patients with cirrhosis without infection admitted at Hallym University Medical Center were enrolled. Adrenal insufficiency was defined as a peak cortisol level < 18 μg/dL, 30 or 60 minutes after 250 μg Synacthen injection.The study included 55 male patients (79.7%), and the mean age was 57.9 ± 12.9 years. Cirrhosis etiology was alcohol consumption, HBV, HCV, both viral and alcohol related, and cryptogenic in 49, 15, 7, 11, 9 patients, respectively. Adrenal insufficiency occurred in 24 patients (34.8%). No differences were found in age, sex, mean arterial pressure, heart rate, HDL, cirrhosis etiology, degree of alcohol consumption, encephalopathy, variceal bleeding history, or hepatocellular carcinoma between patients with or without adrenal insufficiency. Serum albumin level was lower (P < .05), and INR was higher (P < .05) in patients with than in those without adrenal insufficiency. However, multivariate analysis revealed no independent adrenal insufficiency predictor. Significant negative correlations were found between Child-Pugh score and peak cortisol levels (γ=-0.365, P = .008).Adrenal insufficiency was frequent even in hemodynamically stable patients with cirrhosis and tended to be associated with only liver disease severity, being unrelated to cirrhosis etiology.
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Paz-Delgadillo J, Monreal-Robles R, Villarreal-Pérez JZ, Maldonado-Garza HJ, Bosques-Padilla FJ, Lavalle-González FJ. Algorithm for Screening of Adrenal Function in Stable Patients with Cirrhosis. Ann Hepatol 2018; 16:788-796. [PMID: 28809735 DOI: 10.5604/01.3001.0010.2797] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIMS Adrenal insufficiency (AI) is common in patients with cirrhosis. We aimed to assess the presence of AI in stable patients with cirrhosis using the gold-standard insulin tolerance test (ITT) and to propose an algorithm for screening AI in these patients. MATERIAL AND METHODS We studied 40 stable patients with cirrhosis. We determined the basal total (BTC) and peak cortisol (PTC) levels. Using the ITT, we defined AI as a serum PTC < 18 μg/dL at 30 min after insulin-induced hypoglycemia. We assessed the diagnostic accuracy of BTC in different stages of liver disease to discriminate between those with NAF and AI. RESULTS Of the 40 patients, 24 (60%) presented with AI. Child-Pugh and MELD scores differed between the NAF and AI groups (Child-Pugh: NAF 7.2 ± 1.7 vs. AI 8.8 ± 2.4, p = 0.024 and MELD: NAF 9.9 ± 2.5 vs. AI 14.9 ± 6.3, p = 0.001). The BTC level was lower in patients with AI than in those with NAF (7.2 ± 2.4 vs. 12.5 ± 5.2, p < 0.001). A BTC value ≤ 10.0 μg/dL had a 96% sensitivity (negative predictive value: 90%) for identifying AI. This cutoff value (BTC ≤ 10.0 μg/dL) provided 100% specificity (positive predictive value: 100%) in patients with advanced liver disease (Child-Pugh ≥ 9 or MELD ≥ 12). CONCLUSION An algorithm including the use of BTC and the severity of liver disease may be a useful and simple method for assessing adrenal function in stable patients with cirrhosis.
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Affiliation(s)
- Jonathan Paz-Delgadillo
- Universidad Autónoma de Nuevo León, Monterrey, México Gastroenterology Service, Hospital Universitario "Dr. José E. González"
| | - Roberto Monreal-Robles
- Universidad Autónoma de Nuevo León, Monterrey, México Gastroenterology Service, Hospital Universitario "Dr. José E. González"
| | - Jesús Z Villarreal-Pérez
- Universidad Autónoma de Nuevo León, Monterrey, México Endocrinology Service, Hospital Universitario "Dr. José E. González"
| | - Héctor J Maldonado-Garza
- Universidad Autónoma de Nuevo León, Monterrey, México Gastroenterology Service, Hospital Universitario "Dr. José E. González"
| | - Francisco J Bosques-Padilla
- Universidad Autónoma de Nuevo León, Monterrey, Mexico Gastroenterology Division, Hospital Universitario "Dr. José Eleuterio González"
| | - Francisco J Lavalle-González
- Universidad Autónoma de Nuevo León, Monterrey, México Gastroenterology Service, Hospital Universitario "Dr. José E. González"
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Cholongitas E, Goulis I, Pagkalidou E, Haidich A, Karagiannis A, Nakouti T, Pipili C, Oikonomou T, Gerou S, Akriviadis E. Relative Adrenal Insufficiency is Associated with the Clinical Outcome in Patients with Stable Decompensated Cirrhosis. Ann Hepatol 2018; 16:584-590. [PMID: 28611262 DOI: 10.5604/01.3001.0010.0298] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The clinical impact of relative adrenal insufficiency (AI) on patients with stable decompensated cirrhosis (DeCi) has not been yet elucidated. AIM Explore the association between AI and outcome [death or liver transplantation (LT)] in patients with DeCi. MATERIAL AND METHODS Patients with DeCi presenting no active complication have been included. Clinical and laboratory data, including serum levels of corticosteroid-binding globulin (CBG), interleukin (IL)-1b, IL-6 and tumor necrosis factor (TNFα) were recorded in each participant. Salivary cortisol (SC) and serum total cortisol (STC) were assessed at (T0) and 1 h (T60) after intravenous injection of 250 μg corticotropin. RESULTS 113 consecutive patients were totally tested. Median SC was 3.9 ng/mL and 15.5 ng/mL and median STC was 10.7 μg/dL and 22.7 μg/dL at T0 and T60 respectively. The patients with AI [group 1, n = 34 (30%)] had significantly lower systolic blood pressure (106 ± 12 vs. 113 ± 13 mmHg, p = 0.05), serum sodium (133 ± 7 vs. 137 ± 12 mEq/ L, p = 0.04), HDL (29.9 ± 14 vs. 38.6 ± 18 mg/dL, p = 0.034) and albumin (2.7 ± 0.5 vs. 3.1 ± 0.5 g/dL, p = 0.002), but higher direct bilirubin (median: 1.6 vs. 0.8 mg/dL, p = 0.029) compared to those without AI [group 2, n = 79 (70%)]. Moreover, group 1 patients presented more frequently past history of spontaneous bacterial peritonitis (SBP) [10/34 (29.4%) vs. 6/79 (7.5%), p = 0.002]. AI was significantly associated with death [HR = 2.65, 95% C.I.: 1.55 - 4.52, p = 0.003 over a follow up period of 12 (6-48) months.] Conclusions. The presence of AI in patients with stable DeCi predispose to obvious clinical implications since it is associated with circulatory dysfunction, previous history of SBP and worse survival.
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Affiliation(s)
- Evangelos Cholongitas
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
| | - Ioannis Goulis
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
| | - Eirini Pagkalidou
- Department of Hygiene and Epidemiology, School of Medicine, Thessaloniki, Greece
| | - Anna Haidich
- Department of Hygiene and Epidemiology, School of Medicine, Thessaloniki, Greece
| | - Apostolos Karagiannis
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
| | - Theodora Nakouti
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
| | - Chrysoula Pipili
- Division of Nephrology, Queen Elizabeth University Hospital, Glasgow, UK
| | - Theodora Oikonomou
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
| | - Spyros Gerou
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
| | - Evangelos Akriviadis
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
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Nolan BJ, Sorbello J, Brown N, Dimeski G, Inder WJ. Characterization of the serum and salivary cortisol response to the intravenous 250 µg ACTH 1-24 stimulation test. Endocrine 2018; 59:520-528. [PMID: 29299794 DOI: 10.1007/s12020-017-1505-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Accepted: 12/19/2017] [Indexed: 10/18/2022]
Abstract
PURPOSE The ACTH1-24 stimulation test is commonly used to assess the hypothalamic-pituitary-adrenal (HPA) axis. Given variations in CBG concentration and binding affinity, serum total cortisol may misclassify some patients. Salivary cortisol correlates well with serum free cortisol but is easier to measure and widely available in commercial laboratories. The aim of this study was to investigate the utility of measuring salivary cortisol during the ACTH1-24 stimulation test. DESIGN AND METHODS Case-control study in a clinical research facility. Eighty-seven patients with suspected cortisol deficiency, twenty-four healthy controls, and ten healthy women on the oral contraceptive (OC) underwent an intravenous 250 µg ACTH1-24 stimulation test. Concordance of ACTH1-24 stimulated serum and salivary cortisol was evaluated. RESULTS There was a significant difference in serum cortisol between the healthy volunteers and the women on the OC (P < 0.001) but no difference in salivary cortisol. The lower limit of the reference interval for salivary cortisol at 60 min was 26 nmol/L. 27/89 (30%) of tests with suspected HPA axis disorder failed the 60 min serum cortisol cut-off of 500 nmol/L. Of these, 24/27 (89%) had a salivary cortisol of <26 nmol/L. In contrast, 12/19 (63%) tests and 5/43 (12%) tests where the 60 min serum cortisol was 500-599 and ≥600 nmol/L, respectively had a salivary cortisol of <26 nmol/L. CONCLUSIONS Salivary cortisol provides additional diagnostic value during the 250 µg ACTH1-24 stimulation test in patients with proven or suspected alterations in CBG and potentially those with a borderline 60 min serum cortisol 500-599 nmol/L.
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Affiliation(s)
- Brendan J Nolan
- Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Jane Sorbello
- Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Nigel Brown
- Department of Chemical Pathology, Pathology Queensland, Brisbane, QLD, Australia
| | - Goce Dimeski
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Department of Chemical Pathology, Pathology Queensland, Brisbane, QLD, Australia
| | - Warrick J Inder
- Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
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Abnormalities of Lipoprotein Levels in Liver Cirrhosis: Clinical Relevance. Dig Dis Sci 2018; 63:16-26. [PMID: 29177578 DOI: 10.1007/s10620-017-4862-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 11/19/2017] [Indexed: 12/17/2022]
Abstract
Progressive lipoprotein impairment occurs in liver cirrhosis and is associated with increased morbidity and mortality. The present review aims to summarize the current evidence regarding the prognostic value of lipoprotein abnormalities in liver cirrhosis and to address the need of a better prognostic stratification of patients, including lipoprotein profile assessment. Low levels of lipoproteins are usual in cirrhosis. Much evidence supports the prognostic role of hypolipidemia in cirrhotic patients. In particular, hypocholesterolemia represents an independent predictor of survival in cirrhosis. In cirrhotic patients, lipoprotein impairment is associated with several complications: infections, malnutrition, adrenal function, and spur cell anemia. Alterations of liver function are associated with modifications of circulating lipids. Decreased levels of lipoproteins significantly impact the survival of cirrhotic patients and play an important role in the pathogenesis of some cirrhosis-related complications.
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Tana MM, Alao H, Morris N, Bernstein S, Hattenbach J, Rehman RB, Brychta R, Sarkar S, Zhao X, Walter M, Buckley A, Chen K, Rotman Y. Fatigued Patients with Chronic Liver Disease Have Subtle Aberrations of Sleep, Melatonin and Cortisol Circadian Rhythms. FATIGUE : BIOMEDICINE, HEALTH & BEHAVIOR 2017; 6:5-19. [PMID: 30546968 PMCID: PMC6287634 DOI: 10.1080/21641846.2018.1408539] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
AIMS We sought to examine whether disturbances in central and peripheral circadian rhythms were related to the experience of fatigue in patients with chronic liver disease (CLD). METHODS Fatigued and non-fatigued patients with compensated CLD were enrolled in a prospective pilot study. Patients underwent a one week evaluation of free-living sleep and physical activity patterns, followed by a 24-hour admission, during which they underwent serial blood sampling, polysomnography, a 6-minute walk test and continuous core temperature measurements under standardized conditions. Blood samples were analyzed for liver tests, melatonin levels, lipids, and cortisol. Circadian rhythms were analyzed using single cosinor analyses. RESULTS Six fatigued and six non-fatigued patients were studied; five participants had cirrhosis. Fatigue severity was positively associated higher peak melatonin levels (rho=0.59, p=0.04) and a delay in night-time melatonin peak and inversely associated with sleep efficiency (rho=-0.63, p=0.04). Polysomnography, 6-minute walk test, and core temperature measurements did not differ significantly between the fatigued and non-fatigued patients. Although liver enzymes, bilirubin and albumin demonstrated a circadian pattern, it was not associated with fatigue. Fatigued patients showed a blunted and delayed cortisol rhythm and fatigue was strongly correlated with cortisol amplitude (rho=-0.77, p=0.004) and phase (r=-0.66, p=0.02). CONCLUSION Subtle aberrations in melatonin and adrenal circadian rhythms, as well as reduced sleep efficiency, likely contribute to fatigue in patients with CLD. These abnormalities may ultimately be a therapeutic target to improve quality of life for fatigued patients with CLD.
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Affiliation(s)
- Michele M. Tana
- Liver & Energy Metabolism Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
- Division of Gastroenterology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- The UCSF Liver Center, San Francisco, CA, USA
- Co-first authors
| | - Hawwa Alao
- Liver & Energy Metabolism Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
- Co-first authors
| | - Nevitt Morris
- Liver & Energy Metabolism Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Shanna Bernstein
- National Institute of Digestive Diseases and Kidney Diseases, Bethesda, MD, USA
| | - Jacob Hattenbach
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Rahiya B. Rehman
- Liver & Energy Metabolism Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Robert Brychta
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Souvik Sarkar
- Liver & Energy Metabolism Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Xiongce Zhao
- National Institute of Digestive Diseases and Kidney Diseases, Bethesda, MD, USA
| | - Mary Walter
- National Institute of Digestive Diseases and Kidney Diseases, Bethesda, MD, USA
| | - Ashura Buckley
- Sleep and Neurodevelopment Service, Office of the Clinical Director, National Institute of Mental Health, Bethesda, MD, USA
| | - Kong Chen
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Yaron Rotman
- Liver & Energy Metabolism Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
- Co-first authors
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Rakici H. Adrenal Insufficiency in Cirrhosis Patients: Evaluation of 108 Case Series. Euroasian J Hepatogastroenterol 2017; 7:150-153. [PMID: 29201798 PMCID: PMC5670259 DOI: 10.5005/jp-journals-10018-1237] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 08/23/2017] [Indexed: 12/26/2022] Open
Abstract
AIM Adrenal insufficiency (AI) in cirrhosis is an issue that has recently gained momentum. It can be seen in both stable and critically ill (sepsis, septic shock, and gastrointestinal system bleeding) cirrhotic patients. Its prevalence exists in a wide range since standardization of diagnostic methods is lacking. We aimed to scrutinize this issue in a 108 case series. MATERIALS AND METHODS We studied the presence of AI and its stage in patients with cirrhosis and its complications by using cross-sectional study. Standard-dose short synacthen test (SD-SST) was performed in 108 patients that had Child C decompensated cirrhosis without critical illness and it was aimed to determine the prevalence of AI based on basal cortisol, peak cortisol, and delta cortisol (basal total cortisol minus peak cortisol after stimulation) levels. RESULTS The prevalence of AI in cirrhosis was found to be 25% based on basal cortisol level of <140 nmol/L, 22.2% based on delta cortisol level of <250 nmol/L, and 29.6% based on peak cortisol level of <500 nmol/L. CONCLUSION Prevalence of AI shows variation in decompensated cirrhosis without critical illness depending on different measures used. More definite results can be obtained when more standardized criteria are widely put into use.How to cite this article: Rakici H. Adrenal Insufficiency in Cirrhosis Patients: Evaluation of 108 Case Series. Euroasian J Hepato-Gastroenterol 2017;7(2):150-153.
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Affiliation(s)
- Hali Rakici
- Department of Gastroenterology, Recep Tayyip Erdogan Universitesi, Riza, Turkey
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Relative Adrenal Insufficiency in Patients with Cirrhosis: A Systematic Review and Meta-Analysis. Dig Dis Sci 2017; 62:1067-1079. [PMID: 28176190 DOI: 10.1007/s10620-017-4471-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 01/20/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Relative adrenal insufficiency (RAI) is frequently observed in patients with cirrhosis. We sought to identify evidence in the literature regarding the impact of RAI on clinical outcomes in cirrhotic patients. METHODS We conducted a systematic review (SR) and meta-analysis (MA) using the Ovid-MEDLINE, EMBASE, and Cochrane Library databases to identify relevant studies in the literature. RESULTS Of the 182 studies identified, 16 were eligible according to our inclusion criteria. The prevalence of RAI was 49.4% (744/1507), and cirrhotic patients with acute critical illnesses such as sepsis were more likely to have RAI compared to those without critical illnesses (P < 0.001). With respect to clinical outcomes, patients with RAI had poorer survival rates and an increased risk of complications such as bleeding and hepatorenal syndrome compared to those without RAI. Corticosteroid therapy had a beneficial effect on critically ill cirrhotic patients in terms of hospital survival rate. CONCLUSIONS Based on this SR and MA, critically ill patients with cirrhosis have a high risk of RAI, and the presence of RAI is related to a poor prognosis and occurrence of cirrhotic complications.
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Lashari BH, Qamar ZR, Arif Z. Diagnosis and Management of Acute Adrenal Insufficiency in the Hospitalized Patient. CURRENT EMERGENCY AND HOSPITAL MEDICINE REPORTS 2017. [DOI: 10.1007/s40138-017-0123-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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D’Aurizio F, Tozzoli R, Dorizzi RM, Brescia V, Fortunato A, Porzio O, Vitillo M. La diagnostica di laboratorio delle malattie del surrene. Raccomandazioni pratiche per l’insufficienza surrenalica primaria. LA RIVISTA ITALIANA DELLA MEDICINA DI LABORATORIO - ITALIAN JOURNAL OF LABORATORY MEDICINE 2016; 12:234-242. [DOI: 10.1007/s13631-016-0135-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Wald EL, Backer CL, Dearani JA, Li Z, Oliver WC, Crow SS. Total and free cortisol responses and their relation to outcomes after cardiopulmonary bypass in infants. J Thorac Cardiovasc Surg 2016; 153:1155-1163. [PMID: 28024808 DOI: 10.1016/j.jtcvs.2016.11.030] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 10/07/2016] [Accepted: 11/04/2016] [Indexed: 10/20/2022]
Abstract
BACKGROUND Hypothalamic-pituitary-adrenal (HPA) axis dysfunction may be partially responsible for the hemodynamic instability experienced by infants after cardiopulmonary bypass (CPB). We report the full spectrum of the HPA response surrounding CPB for infant congenital cardiac surgery. METHODS We enrolled 84 infants who received 1 mg/kg of dexamethasone before initiation of CPB. Total cortisol (TC), free cortisol (FC), adrenocorticotropic hormone (ACTH), and corticosteroid-binding globulin (CBG) were measured at 3 time points: immediately before CPB (TP1), on intensive care unit arrival (TP2), and at 24 hours after surgery (TP3). A 1-μg ACTH stimulation test was performed at each time point to evaluate adrenal responsiveness. RESULTS Sixty-eight infants completed all study procedures. Levels of TC, FC, CBG, and ACTH decreased significantly between the preoperative and 24-hour postoperative measurements. There were no significant associations between preoperative FC responses and clinical outcomes after adjusting for weight and Risk-Adjusted Scores for Congenital Heart Surgery. Infants with subnormal TC responses to ACTH stimulation (<9 μg/dL) at TP2 had greater fluid requirements (P < .001) and greater chest tube output (P < .001) during the first 24 hours, as well as longer length of stay (LOS) (P = .007). Except for LOS, these differences persisted for infants with subnormal stimulation tests at TP3. CONCLUSIONS We observed a significant decline in all aspects of the HPA axis throughout the first 24 hours after infant CPB. TC and FC levels were not associated with clinical outcomes. Subnormal (Δ <9 μg/dL) TC response to cosyntropin stimulation during the postoperative period was associated with increased fluid resuscitation and greater LOS.
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Affiliation(s)
- Eric L Wald
- Divisions of Critical Care and Cardiology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Ill.
| | - Carl L Backer
- Division of Cardiovascular-Thoracic Surgery, Department of Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Joseph A Dearani
- Division of Cardiothoracic Surgery, Mayo Clinic, Rochester, Minn
| | - Zhuo Li
- Division of Statistics, Mayo Clinic, Rochester, Minn
| | | | - Sheri S Crow
- Division of Pediatric Critical Care, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, Minn
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Bertino G, Privitera G, Purrello F, Demma S, Crisafulli E, Spadaro L, Koukias N, Tsochatzis EA. Emerging hepatic syndromes: pathophysiology, diagnosis and treatment. Intern Emerg Med 2016; 11:905-16. [PMID: 27273018 DOI: 10.1007/s11739-016-1478-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 05/25/2016] [Indexed: 12/11/2022]
Abstract
Liver cirrhosis is a major cause of morbidity and mortality worldwide, mainly due to complications of portal hypertension. In this article, we review the current understanding on the pathophysiology, the diagnostic criteria and the available therapeutic options for patients with emerging hepatic syndromes in cirrhosis, namely the hepatorenal, hepato-adrenal and hepatopulmonary syndrome. The hepatorenal syndrome is a well-recognized complication of advanced cirrhosis and is usually associated with an accelerated course to death unless liver transplantation is performed. The hepatopulmonary syndrome is often missed in the evaluation of patients with cirrhosis; however, early recognition is essential for the efficient management of individual patients. The hepato-adrenal syndrome, although not fully characterized, offers an exciting field for research and potential therapeutic interventions.
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Affiliation(s)
- Gaetano Bertino
- Hepatology Unit, Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Catania, Italy
| | - Graziella Privitera
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi-Nesima, Catania, Italy
| | - Francesco Purrello
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi-Nesima, Catania, Italy
| | - Shirin Demma
- Hepatology Unit, Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Catania, Italy
| | - Emanuele Crisafulli
- Hepatology Unit, Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Catania, Italy
| | - Luisa Spadaro
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi-Nesima, Catania, Italy
| | - Nikolaos Koukias
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK.
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Chiriac Ş, Stanciu C, Negru R, Trifan A. ASSESSMENT OF ADRENOCORTICAL DYSFUNCTION IN PATIENTS WITH STABLE LIVER CIRRHOSIS. ACTA ENDOCRINOLOGICA (BUCHAREST, ROMANIA : 2005) 2016; 12:262-267. [PMID: 31149099 PMCID: PMC6535276 DOI: 10.4183/aeb.2016.262] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Relative adrenal insufficiency (RAI) is common in the setting of critical illness as well as in hemodynamically instable cirrhotic patients with sepsis. Several studies have also shown that RAI is frequent in patients with stable cirrhosis without sepsis. The aim of this study was to prospectively assess the incidence of RAI in patients with stable cirrhosis. PATIENTS AND METHODS Forty-seven patients with hemodynamically stable liver cirrhosis without sepsis were prospectively included. RAI, assessed by using low dose-short Synacthen test (LD-SST), was defined as either a basal total cortisol concentration below 3.6 µg/dL or a peak total serum cortisol ≤ 16 µg/dL at 30 min after stimulation. RESULTS RAI was present in 10 (21.3%) of 47 cirrhotic patients. Peak cortisol level was negatively correlated with the severity of cirrhosis evaluated by Child-Turcotte-Pugh (CTP) (r=-0.46; P=0.001) and Model for End-Stage Liver Disease (MELD) (r=-0.51; P=0.001) scores. The frequency of RAI increased from CTP-A (10%) to CTP-B (30%) to CTP-C (60%). CONCLUSION RAI diagnosed by LD-SST is frequent in patients with stable cirrhosis and is related to the severity of liver disease. Further studies are needed to define clinical importance of RAI in stable cirrhotic patients.
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Affiliation(s)
- Ş. Chiriac
- “Grigore T. Popa” University of Medicine and Pharmacy, Iaşi, Romania
| | - C. Stanciu
- “St. Spiridon” Emergency Hospital - Institute of Gastroenterology and Hepatology, Iaşi, Romania
| | - R. Negru
- “Grigore T. Popa” University of Medicine and Pharmacy, Iaşi, Romania
| | - A. Trifan
- “Grigore T. Popa” University of Medicine and Pharmacy, Iaşi, Romania
- “St. Spiridon” Emergency Hospital - Institute of Gastroenterology and Hepatology, Iaşi, Romania
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Rauschecker M, Abraham SB, Abel BS, Wesley R, Saverino E, Trivedi A, Heller T, Nieman LK. Cosyntropin-Stimulated Serum Free Cortisol in Healthy, Adrenally Insufficient, and Mildly Cirrhotic Populations. J Clin Endocrinol Metab 2016; 101:1075-81. [PMID: 26647150 PMCID: PMC4803155 DOI: 10.1210/jc.2015-2285] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Serum free cortisol (SFF) responses to cosyntropin simulation test (CST) may more accurately assess adrenal function than total cortisol (TF). OBJECTIVE The objective of the study was to evaluate the diagnostic utility of SFF responses during a 250-μg CST. DESIGN We recruited healthy volunteers (HV; n = 27), patients with primary and secondary adrenal insufficiency (n = 19 and n = 24, respectively), and subjects with Child-Pugh class A cirrhosis (CH; n = 15). Each received 250 μg cosyntropin with measurement of ACTH and corticosteroid binding globulin (CBG) at time 0 and TF and SFF at 0, 30, and 60 minutes. Salivary cortisol was measured at all time points in CH subjects. RESULTS Peak SFF and TF were significantly higher in HVs vs both AI groups (P < .05). Peak SFF and TF (6.8 μg/dL vs 2.2 μg/dL; [188 nmol/L vs 62 nmol/L]; P < .01) were significantly higher in the secondary adrenal insufficiency vs primary adrenal insufficiency patients. The optimal peak SFF criterion to identify adrenal insufficiency patients vs HV was 0.9 μg/dL (25 nmol/L) (sensitivity of 95%, specificity of 100%). Mean CBG and albumin levels were similar among all four groups. CH patients had a higher peak SFF than HV (2.4 vs 2.0 μg/dL; P = .02. In the CH patients, peak salivary cortisol levels correlated well with peak SFF (rs = 0.84, P = .005). CBG levels were similar among the groups. CONCLUSION We provide normative data for SFF values in HV and AI during the CST. Normal CBG levels in mild cirrhosis did not affect the interpretation of the CST.
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Affiliation(s)
- Mitra Rauschecker
- Program in Reproductive and Adult Endocrinology (M.R., S.B.A., B.S.A., E.S., L.K.N.), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Biostatistics and Clinical Epidemiology Service (R.W.), Clinical Center, and Translational Hepatology Unit (A.T., T.H.), Liver Diseases Branch, The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
| | - Smita Baid Abraham
- Program in Reproductive and Adult Endocrinology (M.R., S.B.A., B.S.A., E.S., L.K.N.), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Biostatistics and Clinical Epidemiology Service (R.W.), Clinical Center, and Translational Hepatology Unit (A.T., T.H.), Liver Diseases Branch, The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
| | - Brent S Abel
- Program in Reproductive and Adult Endocrinology (M.R., S.B.A., B.S.A., E.S., L.K.N.), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Biostatistics and Clinical Epidemiology Service (R.W.), Clinical Center, and Translational Hepatology Unit (A.T., T.H.), Liver Diseases Branch, The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
| | - Robert Wesley
- Program in Reproductive and Adult Endocrinology (M.R., S.B.A., B.S.A., E.S., L.K.N.), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Biostatistics and Clinical Epidemiology Service (R.W.), Clinical Center, and Translational Hepatology Unit (A.T., T.H.), Liver Diseases Branch, The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
| | - Elizabeth Saverino
- Program in Reproductive and Adult Endocrinology (M.R., S.B.A., B.S.A., E.S., L.K.N.), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Biostatistics and Clinical Epidemiology Service (R.W.), Clinical Center, and Translational Hepatology Unit (A.T., T.H.), Liver Diseases Branch, The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
| | - Apurva Trivedi
- Program in Reproductive and Adult Endocrinology (M.R., S.B.A., B.S.A., E.S., L.K.N.), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Biostatistics and Clinical Epidemiology Service (R.W.), Clinical Center, and Translational Hepatology Unit (A.T., T.H.), Liver Diseases Branch, The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
| | - Theo Heller
- Program in Reproductive and Adult Endocrinology (M.R., S.B.A., B.S.A., E.S., L.K.N.), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Biostatistics and Clinical Epidemiology Service (R.W.), Clinical Center, and Translational Hepatology Unit (A.T., T.H.), Liver Diseases Branch, The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
| | - Lynnette K Nieman
- Program in Reproductive and Adult Endocrinology (M.R., S.B.A., B.S.A., E.S., L.K.N.), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Biostatistics and Clinical Epidemiology Service (R.W.), Clinical Center, and Translational Hepatology Unit (A.T., T.H.), Liver Diseases Branch, The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
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Chawlani R, Arora A, Ranjan P, Sharma P, Tyagi P, Bansal N, Singla V, Arora V, Kotecha HL, Kirnake V, Toshniwal J, Kumar A. Adrenal insufficiency predicts early mortality in patients with cirrhosis. United European Gastroenterol J 2015; 3:529-38. [PMID: 26668746 DOI: 10.1177/2050640614552314] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Adrenal insufficiency (AI), also known as hepato-adrenal syndrome, is a well-known entity in cirrhotic patients. However, factors associated with AI and its effect on survival are still not clear. We determined the prevalence of AI in patients with cirrhosis who had no hemodynamic instability or any acute deterioration, and studied its influence on short-term survival. PATIENTS AND METHODS In consecutive cirrhotic patients, presence of AI was determined either by total serum cortisol <18 µg/dl, 60 minutes after 250 µg synacthen injection, or when the delta-fraction (post-synacthen serum cortisol minus basal serum cortisol) was <9 µg/dl. RESULTS A total of 120 patients were included in the study (median age 50 years (range 27-73), males 87%). The median CTP and MELD scores were 10 (range 6-13) and 20 (range 6-40). The etiology of cirrhosis was alcohol (51%), cryptogenic (28%), viral (19%) and autoimmune (2%). Sixty-nine patients (58%) had AI and the remaining 51 (42%) had normal adrenal function. Serum bilirubin was significantly higher (p < 0.05) in the AI group, and total cholesterol, HDL, LDL and hemoglobin were significantly lower (p < 0.05) in the AI group. CTP score, MELD score, and basal cortisol levels were not different between those with and without AI (p = NS). By 120 days of follow-up, 41 patients had died. Thus, the 120-day survival was 66%, and this was higher in patients without AI than in patients with AI (78% vs 56%; p = 0.019). On multivariate analysis absence of AI, low WBC and low CTP score independently predicted 120-day survival. CONCLUSIONS AI is present in more than half of cirrhotic patients but does not parallel the severity scores of cirrhosis. Its presence predicts early mortality in these patients, and this prediction is independent of CTP or MELD scores.
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Affiliation(s)
- Romesh Chawlani
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Anil Arora
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Piyush Ranjan
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Praveen Sharma
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Pankaj Tyagi
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Naresh Bansal
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Vikas Singla
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Veronica Arora
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Hardik L Kotecha
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Vijendra Kirnake
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Jay Toshniwal
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Ashish Kumar
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
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Fede G, Spadaro L, Privitera G, Tomaselli T, Bouloux PM, Purrello F, Burroughs AK. Hypothalamus-pituitary dysfunction is common in patients with stable cirrhosis and abnormal low dose synacthen test. Dig Liver Dis 2015; 47:1047-51. [PMID: 26364559 DOI: 10.1016/j.dld.2015.08.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Revised: 08/03/2015] [Accepted: 08/11/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Adrenal insufficiency is often present in cirrhosis. We hypothesize that a prolonged adrenocorticotropic hormone (ACTH) stimulus can restore cellular capacity of adrenal glands to secrete cortisol. Aim of our study was to assess adrenal responsiveness to prolonged ACTH stimulation in cirrhotics. METHODS Prospective observational study in 121 consecutively admitted cirrhotic patients undergoing a low dose short synacthen test and plasma ACTH measurement using a chemiluminescence immunoassay. Long synacthen test was performed if the low dose was abnormal. RESULTS 46 patients had abnormal low dose short test (38%), and 29 underwent the long test: 41% showed normal response (Group 1), 55% showed delayed response (Group 2) and 1 had abnormal response (4%). Baseline ACTH levels did not significantly differ between the two groups. Median basal cortisol was higher in Group 1 (296 vs. 198 nmol/L; p=0.02). Using ROC curve basal cortisol <254 nmol/L was associated with a delayed long synacthen test response (AUC 0.78, p=0.001) with good accuracy (sensitivity 67%, specificity 81%). CONCLUSION A delayed cortisol response after a prolonged ACTH stimulation is found in over fifty percent of cirrhotics with abnormal low dose short synacthen test, confirming that the mechanism of hypoadrenalism in these patients could be related both to adrenal cellular dysfunction and hypothalamus-pituitary adrenal axis impairment.
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Affiliation(s)
- Giuseppe Fede
- The Royal Free Sheila Sherlock Liver Centre and Institute of Liver and Digestive Health, University College London and Royal Free Hospital, London, UK; Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi Hospital, Catania, Italy.
| | - Luisa Spadaro
- Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi Hospital, Catania, Italy
| | - Graziella Privitera
- Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi Hospital, Catania, Italy
| | - Tania Tomaselli
- Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi Hospital, Catania, Italy
| | | | - Francesco Purrello
- Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi Hospital, Catania, Italy
| | - Andrew Kenneth Burroughs
- The Royal Free Sheila Sherlock Liver Centre and Institute of Liver and Digestive Health, University College London and Royal Free Hospital, London, UK
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Bae YJ, Kratzsch J. Corticosteroid-binding globulin: modulating mechanisms of bioavailability of cortisol and its clinical implications. Best Pract Res Clin Endocrinol Metab 2015; 29:761-72. [PMID: 26522460 DOI: 10.1016/j.beem.2015.09.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Corticosteroid-binding globulin (CBG) is the principal transport protein of glucocorticoids. Approximately 80-90% of serum cortisol binds to CBG with high affinity and only about 5% of cortisol remain unbound and is considered biologically active. CBG seems to modulate and influence the bioavailability of cortisol to local tissues. In this review, we will discuss physicochemical properties of CBG and structure of CBG in the mechanisms of binding and release of cortisol. This review describes several factors affecting CBG functions, such as genetic factors or temperature. Furthermore, clinical implications of CBG abnormalities and the measurement of CBG and its use for assessment of free cortisol levels are described in this review.
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Affiliation(s)
- Yoon Ju Bae
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Paul-List Strasse 13-15, D-04103, Leipzig, Germany.
| | - Juergen Kratzsch
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Paul-List Strasse 13-15, D-04103, Leipzig, Germany
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47
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Bancos I, Erickson D, Bryant S, Hines J, Nippoldt TB, Natt N, Singh R. PERFORMANCE OF FREE VERSUS TOTAL CORTISOL FOLLOWING COSYNTROPIN STIMULATION TESTING IN AN OUTPATIENT SETTING. Endocr Pract 2015; 21:1353-63. [PMID: 26340138 DOI: 10.4158/ep15820.or] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Free cortisol (FC) is potentially superior to total cortisol (TC) measurements in selected clinical settings; however, the advantages of uniform use of FC in outpatient settings are unclear. The objectives of this study were to describe the dynamic response of FC during cosyntropin stimulation testing (CST) compared to TC and to determine the rates of discordance. METHODS This is a cross-sectional study of 295 stable patients who underwent CST in an outpatient Endocrine Testing Center. The main outcome measures were TC and FC measurements during CST. RESULTS The mean age of the 295 subjects was 49.1 (16.9) years. Of 218 females, 43 were taking estrogen therapy (ET) at the time of testing. Adrenal insufficiency (AI) was diagnosed in 41/295 (14%) patients. The FC concentrations were associated with TC concentrations at baseline (R(2) = 0.77, P<.001), 30 minutes (R(2) = 0.87, P<.001), and 60 minutes (R(2) = 0.90, P<.001). The FC cutoffs for AI were 873 and 1,170 ng/dL at 30 and 60 minutes, respectively. The FC had a more pronounced fold change from baseline to peak than TC (median 3.2 vs. 1.7, P<.001). Both TC and FC at baseline were higher in females on ET compared to those who were not and to males; however, peak TC and FC values were similar. In 3/43 females on ET, FC, and TC results were discordant (P = .003). CONCLUSION We report 99% concordance of TC and FC measurements in a large outpatient cohort. The discordant rates were high in females treated with ET (7%). The FC measurements during CST in females on ET may provide a more rapid and accurate diagnosis of AI.
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48
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Graupera I, Pavel O, Hernandez-Gea V, Ardevol A, Webb S, Urgell E, Colomo A, Llaó J, Concepción M, Villanueva C. Relative adrenal insufficiency in severe acute variceal and non-variceal bleeding: influence on outcomes. Liver Int 2015; 35:1964-73. [PMID: 25644679 DOI: 10.1111/liv.12788] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 01/09/2015] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Relative adrenal insufficiency (RAI) is common in critical illness and in cirrhosis, and is related with worse outcomes. The prevalence of RAI may be different in variceal and non-variceal bleeding and whether it may influence outcomes in these settings is unclear. This study assesses RAI and its prognostic implications in cirrhosis with variceal bleeding and in peptic ulcer bleeding. METHODS Patients with severe bleeding (systolic pressure <100 mmHg and/or haemoglobin <8 g/L) from oesophageal varices or from a peptic ulcer were included. Adrenal function was evaluated within the first 24 h and RAI was diagnosed as delta cortisol <250 nmol/L after 250 μg of i.v. corticotropin. RESULTS Sixty-two patients were included, 36 had cirrhosis and variceal bleeding and 26 without cirrhosis had ulcer bleeding. Overall, 15 patients (24%) had RAI, 8 (22%) with variceal and 7 (24%) with ulcer bleeding. Patients with RAI had higher rate of bacterial infections. Baseline serum and salivary cortisol were higher in patients with RAI (P < 0.001) while delta cortisol was lower (P < 0.001). There was a good correlation between plasma and salivary cortisol (P < 0.001). The probability of 45-days survival without further bleeding was lower in cirrhotic patients with variceal bleeding and RAI than in those without RAI (25% vs 68%, P = 0.02), but not in non-cirrhotic patients with peptic ulcer bleeding with or without RAI (P = 0.75). CONCLUSION The prevalence of RAI is similar in ulcer bleeding and in cirrhosis with variceal bleeding. Cirrhotic patients with RAI, but not those with bleeding ulcers, have worse prognosis.
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Affiliation(s)
- Isabel Graupera
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona Autonomous University, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Oana Pavel
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona Autonomous University, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Virginia Hernandez-Gea
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona Autonomous University, Barcelona, Spain
| | - Alba Ardevol
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona Autonomous University, Barcelona, Spain
| | - Susan Webb
- Department of Endocrinology, Hospital de la Santa Creu i Sant Pau, Barcelona Autonomous University, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Barcelona, Spain
| | - Eulalia Urgell
- Department of Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona Autonomous University, Barcelona, Spain
| | - Alan Colomo
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona Autonomous University, Barcelona, Spain
| | - Jordina Llaó
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona Autonomous University, Barcelona, Spain
| | - Mar Concepción
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona Autonomous University, Barcelona, Spain
| | - Càndid Villanueva
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona Autonomous University, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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49
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Molenaar N, Groeneveld ABJ, de Jong MFC. Three calculations of free cortisol versus measured values in the critically ill. Clin Biochem 2015; 48:1053-8. [PMID: 26169244 DOI: 10.1016/j.clinbiochem.2015.07.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 07/03/2015] [Accepted: 07/08/2015] [Indexed: 10/23/2022]
Abstract
OBJECTIVES To investigate the agreement between the calculated free cortisol levels according to widely applied Coolens and adjusted Södergård equations with measured levels in the critically ill. DESIGN AND METHODS A prospective study in a mixed intensive care unit. We consecutively included 103 patients with treatment-insensitive hypotension in whom an adrenocorticotropic hormone (ACTH) test (250μg) was performed. Serum total and free cortisol (equilibrium dialysis), corticosteroid-binding globulin and albumin were assessed. Free cortisol was estimated by the Coolens method (C) and two adjusted Södergård (S1 and S2) equations. Bland Altman plots were made. RESULTS The bias for absolute (t=0, 30 and 60min after ACTH injection) cortisol levels was 38, -24, 41nmol/L when the C, S1 and S2 equations were used, with 95% limits of agreement between -65-142, -182-135, and -57-139nmol/L and percentage errors of 66, 85, and 64%, respectively. Bias for delta (peak-baseline) cortisol was 14, -31 and 16nmol/L, with 95% limits of agreement between -80-108, -157-95, and -74-105nmol/L, and percentage errors of 107, 114, and 100% for C, S1 and S2 equations, respectively. CONCLUSIONS Calculated free cortisol levels have too high bias and imprecision to allow for acceptable use in the critically ill.
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Affiliation(s)
- Nienke Molenaar
- Department of Surgery, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
| | - A B Johan Groeneveld
- Department of Intensive Care, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands
| | - Margriet F C de Jong
- Department of Nephrology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.
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50
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Karagiannis AKA, Nakouti T, Pipili C, Cholongitas E. Adrenal insufficiency in patients with decompensated cirrhosis. World J Hepatol 2015; 7:1112-1124. [PMID: 26052400 PMCID: PMC4450188 DOI: 10.4254/wjh.v7.i8.1112] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Revised: 01/12/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Adrenal reserve depletion and overstimulation of the hypothalamus-pituitary-adrenal (HPA) axis are causes for adrenal insufficiency (AI) in critically ill individuals. Cirrhosis is a predisposing condition for AI in cirrhotics as well. Both stable cirrhotics and liver transplant patients (early and later after transplantation) have been reported to present AI. The mechanisms leading to reduced cortisol production in cirrhotics are the combination of low cholesterol levels (the primary source of cortisol), the increased cytokines production that overstimulate and exhaust HPA axis and the destruction of adrenal glands due to coagulopathy. AI has been recorded in 10%-82% cirrhotics depending on the test used to evaluate adrenal function and in 9%-83% stable cirrhotics. The similarity of those proportions support the assumption that AI is an endogenous characteristic of liver disease. However, the lack of a gold standard method for AI assessment and the limitation of precise thresholds in cirrhotics make difficult the recording of the real prevalence of AI. This review aims to summarize the present data over AI in stable, critically ill cirrhotics and liver transplant recipients. Moreover, it provides information about the current knowledge in the used diagnostic tools and the possible effectiveness of corticosteroids administration in critically ill cirrhotics with AI.
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