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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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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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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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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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Praharaj DL, Anand AC. Clinical Implications, Evaluation, and Management of Hyponatremia in Cirrhosis. J Clin Exp Hepatol 2022; 12:575-594. [PMID: 35535075 PMCID: PMC9077240 DOI: 10.1016/j.jceh.2021.09.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/06/2021] [Indexed: 02/06/2023] Open
Abstract
Hyponatremia is the most common electrolyte abnormality in patients with decompensated cirrhosis on Liver Transplantation (LT) waiting list. Most of these patients have dilutional or hypervolemic hyponatremia secondary to splanchnic vasodilatation. Excessive secretion of the antidiuretic hormone also plays an important role. Hypervolemic hyponatremia is commonly associated with refractory ascites, spontaneous bacterial peritonitis, and hepatic encephalopathy. Although uncommon, the use of diuretics and laxatives can cause hypovolemic hyponatremia that is characterized by the striking absence of ascites or pedal edema. Clinical features are often nonspecific and depend on the acuity of onset rather than the absolute value of serum sodium. Symptoms may be subtle, including nausea, lethargy, weakness, or anorexia. However, rarely patients may present with confusion, seizures, psychosis, or coma. Treatment includes discontinuation of diuretics, beta-blockers, and albumin infusion. Hypertonic saline (3%) infusion may be used in patients with very low serum sodium (<110 mmol/L) or when patients present with seizures or coma. Short-term use of Vasopressin (V2) receptor antagonists may also be used to normalize sodium levels prior to LT. However, all these measures may be futile, and LT remains the definite treatment in these patients to improve survival. In this review, we describe the classification, pathogenesis of hyponatremia, and its clinical implications in patients with cirrhosis. Approach to these patients along with management will also be discussed briefly.
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Key Words
- ACE, angiotensin-converting enzyme
- ACLF, acute-on-chronic liver failure
- ACTH, adrenocorticotropic hormone
- ADH
- ADH, antidiuretic hormone
- AKI, acute kidney injury
- AVP, arginine vasopressin
- CLIF, chronic liver failure
- CNS, central nervous system
- CTP, Child-Turcotte-Pugh
- CVVHD, continuous venovenous hemofiltration
- DAMP, damage-associated molecular patterns
- EABV, effective arterial blood volume
- FENa, fractional excretion of sodium
- HE, hepatic encephalopathy
- HRS, hepatorenal syndrome
- LT, liver transplantation
- LVP, large volume paracentesis
- MAP, mean arterial pressure
- MELD, model of end-stage liver disease
- NO, nitric oxide
- NSBB, nonselective beta-blockers
- PAMP, pathogen-associated molecular patterns
- PICD, paracentesis-induced circulatory dysfunction
- PPCD, post-paracentesis circulatory dysfunction
- PRA, plasma renin activity
- RA, refractory ascites
- RAAS, renin-angiotensin-aldosterone-system
- RAI, relative adrenal insufficiency
- RBF, renal blood flow
- SBP, spontaneous bacterial peritonitis
- SIADH, syndrome of inappropriate ADH secretion
- SMT, standard medical treatment
- SNS, sympathetic nervous system
- TBW, total body water
- TIPS, transjugular intrahepatic portosystemic shunt
- advanced cirrhosis
- albumin
- hyponatremia
- liver transplantation
- sNa, serum sodium
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Affiliation(s)
- Dibya L. Praharaj
- Address for correspondence. Dibya L Praharaj, Assistant Professor, Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Science, Bhubaneswar, India
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Relative Adrenal Insufficiency in Decompensated Cirrhotic Children: Does It Affect Outcome? Am J Gastroenterol 2022; 117:120-128. [PMID: 34506335 DOI: 10.14309/ajg.0000000000001486] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 08/03/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Relative adrenal insufficiency (RAI) is associated with poor outcome in adult cirrhotics. So far, pediatric studies are not available on the same. We aimed to prospectively study the presence and outcome of RAI in children with decompensated cirrhosis over 180 days. METHODS Hemodynamically stable children with decompensated cirrhosis were sampled for serum basal cortisol and peak cortisol (after 30 minutes of 1-μg intravenous Synacthen) at day 1 and day 21. RAI was diagnosed as peak cortisol <500 nmol/L. Serum cytokines (interleukin-6 and tumor necrosis factor-α) and lipid profile were correlated with RAI. Cohort was followed up for outcomes over 180 days for complications and survival. With the identified risk factors, prognostic models were derived and compared with pediatric end-stage liver disease (PELD) and Child-Turcotte-Pugh scores. RESULTS Prevalence of RAI was 54% at baseline and 61% at day 21 in the enrolled patients (n = 63, aged 128 ± 48 months, male 78%). No significant differences in cytokines and serum lipid levels were seen between RAI and normal adrenal function groups. Patients with RAI at baseline (D1-RAI) developed higher complications at follow-up as compared to the normal adrenal function group (53% vs 24%, P = 0.02). The PELD score (odds ratio 1.08, confidence interval 1.05-1.12, P < 0.01) and D1-RAI (odds ratio 3.19, confidence interval 1.32-7.73, P = 0.01) were independent predictors of follow-up complications. The PELD-delta cortisol model (area under the receiver operating curve 0.84, P < 0.001, 92% sensitivity; 60% specificity) predicted morbidity better than isolated PELD or Child-Turcotte-Pugh scores. DISCUSSION RAI is a risk factor for development of complications in pediatric cirrhosis over short-term follow-up. The PELD-delta cortisol score is a promising prognostic model for predicting follow-up complications.
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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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Chen X, Chai Y, Wang SB, Wang JC, Yue SY, Jiang RC, Zhang JN. Risk factors for corticosteroid insufficiency during the sub-acute phase of acute traumatic brain injury. Neural Regen Res 2020; 15:1259-1265. [PMID: 31960811 PMCID: PMC7047797 DOI: 10.4103/1673-5374.272611] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hypothalamic-pituitary-adrenal axis dysfunction may lead to the occurrence of critical illness-related corticosteroid insufficiency. Critical illness-related corticosteroid insufficiency can easily occur after traumatic brain injury, but few studies have examined this occurrence. A multicenter, prospective, cohort study was performed to evaluate the function of the hypothalamic-pituitary-adrenal axis and the incidence of critical illness-related corticosteroid insufficiency during the sub-acute phase of traumatic brain injury. One hundred and forty patients with acute traumatic brain injury were enrolled from the neurosurgical departments of three tertiary-level hospitals in China, and the critical illness-related corticosteroid insufficiency incidence, critical-illness-related corticosteroid insufficiency-related risk factors, complications, and 28-day mortality among these patients was recorded. Critical illness-related corticosteroid insufficiency was diagnosed in patients with plasma total cortisol levels less than 10 μg/dL (275.9 nM) on post-injury day 4 or when serum cortisol was insufficiently suppressed (less than 50%) during a dexamethasone suppression test on post-injury day 5. The results demonstrated that critical illness-related corticosteroid insufficiency occurred during the sub-acute phase of traumatic brain injury in 5.6% of patients with mild injury, 22.5% of patients with moderate injury, and 52.2% of patients with severe injury. Traumatic brain injury-induced critical illness-related corticosteroid insufficiency was strongly correlated to injury severity during the sub-acute stage of traumatic brain injury. Traumatic brain injury patients with critical illness-related corticosteroid insufficiency frequently presented with hemorrhagic cerebral contusions, diffuse axonal injury, brain herniation, and hypotension. Differences in the incidence of hospital-acquired pneumonia, gastrointestinal bleeding, and 28-day mortality were observed between patients with and without critical illness-related corticosteroid insufficiency during the sub-acute phase of traumatic brain injury. Hypotension, brain-injury severity, and the types of traumatic brain injury were independent risk factors for traumatic brain injury-induced critical illness-related corticosteroid insufficiency. These findings indicate that critical illness-related corticosteroid insufficiency is common during the sub-acute phase of traumatic brain injury and is strongly associated with poor prognosis. The dexamethasone suppression test is a practical assay for the evaluation of hypothalamic-pituitary-adrenal axis function and for the diagnosis of critical illness-related corticosteroid insufficiency in patients with traumatic brain injury, especially those with hypotension, hemorrhagic cerebral contusions, diffuse axonal injury, and brain herniation. Sub-acute infection of acute traumatic brain injury may be an important factor associated with the occurrence and development of critical illness-related corticosteroid insufficiency. This study protocol was approved by the Ethics Committee of General Hospital of Tianjin Medical University, China in December 2011 (approval No. 201189).
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Affiliation(s)
- Xin Chen
- Department of Neurosurgery, General Hospital of Tianjin Medical University, Tianjin, China
| | - Yan Chai
- Tianjin Neurological Institute; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China
| | - Shao-Bo Wang
- Department of Neurosurgery, Ordos Central Hospital, Ordos, Inner Mongolia Autonomous Region, China
| | - Jia-Chong Wang
- Department of Neurosurgery, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Changsha, Hunan Province, China
| | - Shu-Yuan Yue
- Department of Neurosurgery, General Hospital of Tianjin Medical University, Tianjin, China
| | - Rong-Cai Jiang
- Department of Neurosurgery, General Hospital of Tianjin Medical University, Tianjin, China
| | - Jian-Ning Zhang
- Tianjin Neurological Institute; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China
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Nandish HK, Arun CS, Nair HR, Gopalakrishna R, Kumar H, Venu RP. Adrenal insufficiency in decompensated cirrhotic patients without infection: prevalence, predictors and impact on mortality. J R Coll Physicians Edinb 2019; 49:277-281. [PMID: 31808452 DOI: 10.4997/jrcpe.2019.405] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Relative adrenal insufficiency (RAI) is common in compensated and decompensated chronic liver disease in the presence of sepsis. This study was performed to find out the prevalence of RAI in decompensated cirrhotic patients presenting with hepatic encephalopathy and variceal bleeding without any evidence of infection. METHODS The study prospectively included 75 cirrhotic patients with signs of decompensation. The short Synacthen test (SST) was performed on all patients after ruling out infection. Patients with positive blood, urine, sputum, ascitic and pleural fluid cultures or evidence of infection on chest X-ray and those with elevated procalcitonin levels (>0.05 ng/ml) were excluded. RAI in critical illness was defined by a delta cortisol level (difference between basal and post-stimulation cortisol) of ≤9 μg/dl after SST. RESULTS The mean age of the study population was 54 ± 11 years. Upper gastrointestinal bleed and hepatic encephalopathy were seen in 56.6% and 41.5%, respectively, and both were seen in 1.9%. Of the 75 patients, 55 (73%) were in Child-Turcotte-Pugh (CTP) class C and the mean model for end-stage liver disease (MELD) score was 21 ± 7. Forty-five patients (60%) met our criteria for RAI. Those with RAI had lower serum albumin (2.4 ± 0.5 g/dl vs 2.7 ± 0.5 g/dl, p = 0.03) and higher MELD scores (22 ± 7 vs 19 ± 6, p = 0.03). Prevalence of RAI in CTP class C was 65% (36 out of 55 patients) compared to 45% (9 out of 20 patients) in Child-Pugh stage A and B. Similarly, 82% (23 out of 28 patients) with MELD scores >25 had RAI compared to 54% with MELD scores <20. None of biochemical parameters were predictive of RAI on logistic regression analysis. Three-month mortality rate was not significantly different in patients with or without adrenal insufficiency (44% vs 28%, p = 0.11). CONCLUSION The present study showed RAI to be common in noninfected decompensated cirrhotic patients, but did not predict 3-month mortality. There were no other predictive factors in those with RAI. Hence, in patients with cirrhosis without infection, the clinical utility of routine adrenal function testing needs further elucidation.
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Affiliation(s)
- Hullenahalli K Nandish
- Centre for Liver Diseases, Digestive Diseases Institute, Amrita Institute of Medical Sciences, Kerala, India
| | - Chankramath S Arun
- Department of Endocrinology, Amrita Institute of Medical Sciences, Ponekkara, Kochi-41, India,
| | - Harikumar R Nair
- Centre for Liver Diseases, Digestive Diseases Institute, Amrita Institute of Medical Sciences, Kerala, India
| | - Rajesh Gopalakrishna
- Centre for Liver Diseases, Digestive Diseases Institute, Amrita Institute of Medical Sciences, Kerala, India
| | - Harish Kumar
- Department of Endocrinology and Metabolism, Amrita Institute of Medical Sciences, Kerala, India
| | - Rama P Venu
- Centre for Liver Diseases, Digestive Diseases Institute, Amrita Institute of Medical Sciences, Kerala, India
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11
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Levick C, Aspinall RJ. Prevalence and clinical significance of relative adrenal insufficiency in decompensated cirrhosis. J R Coll Physicians Edinb 2019; 49:274-276. [PMID: 31808451 DOI: 10.4997/jrcpe.2019.404] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025] Open
Affiliation(s)
- Christina Levick
- Department of Gastroenterology and Hepatology, Portsmouth Hospitals NHS Trust, Queen Alexandra Hospital, Portsmouth, UK
| | - Richard J Aspinall
- Department of Gastroenterology and Hepatology, Portsmouth Hospitals NHS Trust, Queen Alexandra Hospital, Portsmouth PO6 3LY, UK,
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12
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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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13
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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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14
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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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15
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Moini M, Yazdani Sarvestani M, Shams M, Nomovi M. Evaluation of Adrenal Function in Nonhospitalized Patients with Cirrhosis. Can J Gastroenterol Hepatol 2017; 2017:2354253. [PMID: 28812008 PMCID: PMC5546071 DOI: 10.1155/2017/2354253] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 06/09/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Patients with cirrhosis and advancing hepatic insufficiency may show various degrees of other organ malfunction, including brain, kidney, and lung. Several studies have also shown a high prevalence of adrenal insufficiency in cirrhotic patients that may cause hemodynamic instability. MATERIALS AND METHODS In this study we prospectively evaluated adrenal function in a population of nonhospitalized cirrhotic patients. Categorization of liver disease severity was done according to model for end-stage liver disease (MELD) score. Adrenocorticotropic hormone stimulation testing was performed on subjects using 250 μg of synthetic short acting hormone; radio immunoassay was used to measure plasma cortisol levels. RESULTS Of 105 cirrhotic patients, 15.23% had evidence of adrenal insufficiency. These patients were not statistically different from those with normal adrenal function in levels of serum creatinine or bilirubin, MELD score, or presence of cirrhosis related complications. Significant differences were seen in mean international normalized ratio and serum sodium. Patients with a sodium level < 135 mEq/L had a higher rate (31.25%) of adrenal insufficiency. CONCLUSION Adrenal dysfunction was identified in a population of stable nonhospitalized cirrhotic patients. Our results suggest a possible role for adrenal dysfunction as a contributing factor in hyponatremia in cirrhosis independent of other known factors of neurohormonal activation secondary to systemic vasodilation.
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Affiliation(s)
- Maryam Moini
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Nemazee Hospital, Zand Street, Shiraz 71935-1311, Iran
| | - Mitra Yazdani Sarvestani
- Department of Internal Medicine, Fasa University of Medical Sciences, Ebne Sina Square, Fasa, Iran
| | - Mesbah Shams
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Masood Nomovi
- Department of Internal Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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16
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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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17
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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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18
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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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19
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Yamashita M, Kageyama K, Murakami H, Sugiyama A, Yanagimachi M, Sato E, Murasawa S, Matsui J, Tamasawa N, Daimon M. The Evaluation of Adrenal Function in Two Cases of Hypocortisolism Accompanied by Liver Cirrhosis. Intern Med 2016; 55:765-8. [PMID: 27041161 DOI: 10.2169/internalmedicine.55.5604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Adrenal insufficiency may occur in patients with liver cirrhosis. The assessment of hypothalamus-pituitary-adrenal function is important in such patients, but there is no consensus as to how it should be performed. We herein report the results of our evaluation of the adrenal function in two patients with hypocortisolism accompanied by liver cirrhosis. The patients lacked the typical features of hypocortisolism. One was diagnosed with hypocortisolism accompanied by liver cirrhosis while the other had secondary adrenal insufficiency caused by a hypothalamic disorder. Hypocortisolism accompanied by liver cirrhosis should be evaluated by endocrine tests to determine its pathogenesis. A low-dose adrenocorticotropic hormone test may be appropriate for non-critically ill cirrhotic patients.
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Affiliation(s)
- Maki Yamashita
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Japan
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20
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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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21
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Kalafateli M, Triantos C. Relative adrenal insufficiency in patients with cirrhosis and variceal bleeding. Liver Int 2015; 35:2202. [PMID: 25765853 DOI: 10.1111/liv.12820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Affiliation(s)
- Maria Kalafateli
- Department of Gastroenterology, University Hospital of Patras, Patras, Greece
| | - Christos Triantos
- Department of Gastroenterology, University Hospital of Patras, Patras, Greece
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22
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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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23
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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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24
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Anastasiadis SN, Giouleme OI, Germanidis GS, Vasiliadis TG. Relative adrenal insufficiency in cirrhotic patients. CLINICAL MEDICINE INSIGHTS. GASTROENTEROLOGY 2015; 8:13-7. [PMID: 25780347 PMCID: PMC4348066 DOI: 10.4137/cgast.s18127] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 09/19/2014] [Accepted: 10/12/2014] [Indexed: 12/19/2022]
Abstract
Relative adrenal insufficiency (RAI) was demonstrated in patients with cirrhosis and liver failure. A relationship appears to exist between the severity of the liver disease and the presence of RAI. Neither the mechanism nor the exact prevalence of RAI is fully understood. There is though a hypothesis that low high-density lipoprotein (HDL) levels in this group of patients may be responsible for the insufficiency of cortisol. Several questions also arise about the way and the kind of cortisol (total cortisol, free cortisol, or even salivary cortisol) that should be measured. The presence of RAI in patients with cirrhosis is unquestionable, but still several studies should come up in order to properly define it and fully understand it.
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Affiliation(s)
- Sotirios N Anastasiadis
- 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Greece
| | - Olga I Giouleme
- 2nd Prop. Clinic of Internal Medicine, Hippokration Hospital, Aristotle University of Thessaloniki, Greece
| | - Georgios S Germanidis
- 1st Department of Internal Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Greece
| | - Themistoklis G Vasiliadis
- 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Greece
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Egerod Israelsen M, Gluud LL, Krag A. Acute kidney injury and hepatorenal syndrome in cirrhosis. J Gastroenterol Hepatol 2015; 30:236-43. [PMID: 25160511 DOI: 10.1111/jgh.12709] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/04/2014] [Indexed: 12/11/2022]
Abstract
Cirrhosis is the eighth leading cause of "years of lost life" in the United States and accounts for approximately 1% to 2% of all deaths in Europe. Patients with cirrhosis have a high risk of developing acute kidney injury. The clinical characteristics of hepatorenal syndrome (HRS) are similar to prerenal uremia, but the condition does not respond to volume expansion. HRS type 1 is rapidly progressive whereas HRS type 2 has a slower course often associated with refractory ascites. A number of factors can precipitate HRS such as infections, alcoholic hepatitis, and bleeding. The monitoring, prevention, early detection, and treatment of HRS are essential. This paper reviews the value of early evaluation of renal function based on two new sets of diagnostic criteria. Interventions for HRS type 1 include terlipressin combined with albumin. In HRS type 2, transjugular intrahepatic portosystemic shunt (TIPS) should be considered. For both types of HRS patients should be evaluated for liver transplantation.
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Affiliation(s)
- Mads Egerod Israelsen
- Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
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Critical illness-related corticosteroid insufficiency in cirrhotic patients with acute gastroesophageal variceal bleeding: risk factors and association with outcome*. Crit Care Med 2015; 42:2546-55. [PMID: 25083978 DOI: 10.1097/ccm.0000000000000544] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Critical illness-related corticosteroid insufficiency can adversely influence the prognosis of critically ill patients. However, its impact on the outcomes of patients with cirrhosis and acute gastroesophageal variceal bleeding remains unknown. We evaluated adrenal function using short corticotropin stimulation test in patients with cirrhosis and gastroesophageal variceal bleeding. The main outcomes analyzed were 5-day treatment failure and 6-week mortality. DESIGN Prospective observational study. SETTING Ten-bed gastroenterology-specific medical ICU at a 3,613-bed university teaching hospital in Taiwan. PATIENTS Patients with liver cirrhosis and acute gastroesophageal variceal bleeding. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We evaluated adrenal function using short corticotropin stimulation test in 157 episodes of gastroesophageal variceal bleeding in 143 patients with cirrhosis. Critical illness-related corticosteroid insufficiency occurred in 29.9% of patients. The patients with critical illness-related corticosteroid insufficiency had higher rates of treatment failure and 6-week mortality (63.8% vs 10.9%, 42.6% vs 6.4%, respectively; p < 0.001). The cumulative rates of survival at 6 weeks were 57.4% and 93.6% for the critical illness-related corticosteroid insufficiency group and normal adrenal function group, respectively (p < 0.001). The cortisol response to corticotropin was inversely correlated with Model for End-Stage Liver Disease and Child-Pugh scores and positively correlated with the levels of high-density lipoprotein and total cholesterol. Hypovolemic shock, high-density lipoprotein, platelet count, and bacterial infection at inclusion are independent factors predicting critical illness-related corticosteroid insufficiency, whereas critical illness-related corticosteroid insufficiency, Model for End-Stage Liver Disease score, hypovolemic shock, hepatocellular carcinoma, and active bleeding at endoscopy are independent factors to predict treatment failure. Multivariate analysis also identified Model for End-Stage Liver Disease score, hypovolemic shock, and bacterial infection at inclusion as independent factors associated with 6-week mortality. CONCLUSIONS Critical illness-related corticosteroid insufficiency is common in cirrhotic patients with acute gastroesophageal variceal bleeding and is an independent factor to predict 5-day treatment failure.
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Jang JY, Kim TY, Sohn JH, Lee TH, Jeong SW, Park EJ, Lee SH, Kim SG, Kim YS, Kim HS, Kim BS. Relative adrenal insufficiency in chronic liver disease: its prevalence and effects on long-term mortality. Aliment Pharmacol Ther 2014; 40:819-26. [PMID: 25078874 DOI: 10.1111/apt.12891] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 04/29/2014] [Accepted: 07/07/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND The relationship between relative adrenal insufficiency (RAI) and chronic liver disease is unclear. AIM To determine the frequency with which RAI is observed in noncritically ill patients at various stages of chronic liver disease, and the correlation between RAI and disease severity and long-term mortality. METHODS In total, 71 non-critically ill patients with liver cirrhosis (n = 54) and chronic hepatitis (n = 17) were evaluated prospectively. A short stimulation test (SST) with 250 μg of corticotrophin was performed to detect RAI. RAI was defined as an increase in serum cortisol of <9 μg/dL in patients with a basal total cortisol of <35 μg/dL. RESULTS RAI was observed in only 13 (24.1%) of 54 patients with cirrhosis. Compared to those without RAI, cirrhotic patients with RAI had significantly higher Child-Turcotte-Pugh score (10.3 ± 1.7 vs. 7.1 ± 1.8, mean ± s.d., P < 0.001) and Model for End-Stage Liver Disease score (14.5 ± 6.6 vs. 9.4 ± 3.7, P = 0.017). The cortisol response to corticotropin was negatively correlated with the severity of cirrhosis (P < 0.05). In addition, the mortality rate was higher in cirrhotic patients with RAI (69.2%) than in those without RAI (4.9%; P < 0.001) during the follow-up period of 20.1 ± 13.5 months (range, 5.8-51.1 months). The cumulative 1-year survival rates in cirrhotic patients with and without RAI were 69.2% and 95.0%, respectively (P = 0.05), while the corresponding cumulative 3-year survival rates were 0% and 95.0% (P < 0.001). CONCLUSIONS Relative adrenal insufficiency is more commonly observed in those with severe cirrhosis, and is clearly associated with more advanced liver disease and a shortened long-term survival. This suggests that relative adrenal insufficiency is an independent prognostic factor in non-critically ill patients with cirrhosis.
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Affiliation(s)
- J Y Jang
- Division of Gastroenterology, Department of Internal Medicine, Digestive Disease Center, Institute for Digestive Research, College of Medicine, Soonchunhyang University, Seoul, South Korea
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Triantos CK, Kalafateli M, Samonakis D, Zisimopoulos K, Papiamonis N, Sapountzis A, Michalaki M, Theocharis G, Thomopoulos K, Labropoulou-Karatza C, Kyriazopoulou V, Jelastopulu E, Kouroumalis EA, Nikolopoulou V, Burroughs AK. Higher free serum cortisol is associated with worse survival in acute variceal bleeding because of cirrhosis: a prospective study. Eur J Gastroenterol Hepatol 2014; 26:1125-1132. [PMID: 25089543 DOI: 10.1097/meg.0000000000000158] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Critical illness-related corticosteroid insufficiency has been reported in acute variceal bleeding (AVB). In cirrhosis, free serum cortisol (FC) is considered optimal to assess adrenal function. Salivary cortisol (SC) is considered a surrogate for FC. We evaluated FC and its prognostic role in AVB. METHODS Total serum cortisol, SC, cortisol-binding globulin, and FC (Coolens' formula) were evaluated in AVB (n=38) and in stable cirrhosis (CC) (n=31). A Cox proportional hazards model was evaluated for 6-week survival. RESULTS In AVB, the median FC and SC levels were higher with worse liver dysfunction [Child-Pugh (CP) A/B/C: 1.59/2.62/3.26 μg/dl, P=0.019; CPA/B/C: 0.48/0.897/1.81 μg/ml, P<0.001, respectively]. In AVB compared with CC, median total serum cortisol: 24.3 versus 11.6 μg/dl (P<0.001), SC: 0.86 versus 0.407 μg/ml (P<0.001); FC 2.4 versus 0.57 μg/dl (P<0.001). In AVB, 5-day rebleeding was 10.5%, and 6-week and total mortality were 21.1 and 23.7%, respectively. Independent associations with 6-week mortality in AVB were FC at least 3.2 μg/dl (P<0.001), hepatocellular carcinoma (P<0.001), CPC (P<0.001), and early rebleeding (P<0.001). Among patients with normal cortisol-binding globulin (n=14) and albumin (n=31), the factors were hepatocellular carcinoma (P=0.003), CP (P=0.003), and FC (P=0.036). SC was also found to be an independent predictor of 6-week mortality (P<0.001). Area under the curve of FC for predicting 6-week mortality was 0.79. CONCLUSION Higher FC is present in cirrhosis with AVB compared with CC and is associated independently with bleeding-related mortality. However, whether high FC solely indicates the severity of illness or whether there is significant adrenal insufficiency cannot be discerned.
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Affiliation(s)
- Christos K Triantos
- Departments of aGastroenterology bEndocrinology cInternal Medicine, University Hospital of Patras dDepartment of Public Health, Medical School, University of Patras, Patras eDepartment of Gastroenterology, University Hospital of Heraklion, Heraklion, Greece fThe Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
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Acevedo J, Fernández J. New determinants of prognosis in bacterial infections in cirrhosis. World J Gastroenterol 2014; 20:7252-7259. [PMID: 24966596 PMCID: PMC4064071 DOI: 10.3748/wjg.v20.i23.7252] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/09/2014] [Accepted: 05/12/2014] [Indexed: 02/06/2023] Open
Abstract
Despite major advances in the knowledge and management of liver diseases achieved in recent decades, decompensation of cirrhosis still carries a high burden of morbidity and mortality. Bacterial infections are one of the main causes of decompensation. It is very important for clinical management to be aware of the population with the highest risk of poor outcome. This review deals with the new determinants of prognosis in patients with cirrhosis and bacterial infections reported recently. Emergence of multiresistant bacteria has led to an increasing failure rate of the standard empirical antibiotic therapy recommended by international guidelines. Moreover, it has been recently reported that endothelial dysfunction is associated with the degree of liver dysfunction and, in infected patients, with the degree of sepsis. It has also been reported that relative adrenal insufficiency is frequent in the non-critically ill cirrhotic population and it is associated with a higher risk of developing infection, severe sepsis, hepatorenal syndrome and death. We advise a change in the standard empirical antibiotic therapy in patients with high risk for multiresistant infections and also to take into account endothelial and adrenal dysfunction in prognostic models in hospitalized patients with decompensated cirrhosis.
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The incidence of critical-illness-related-corticosteroid-insufficiency is associated with severity of traumatic brain injury in adult rats. J Neurol Sci 2014; 342:93-100. [PMID: 24819916 DOI: 10.1016/j.jns.2014.04.032] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 04/15/2014] [Accepted: 04/22/2014] [Indexed: 12/13/2022]
Abstract
Traumatic brain injury (TBI) causes deleterious critical-illness-related-corticosteroid-insufficiency (CIRCI), leading to high mortality and morbidity. However, the incidence of CIRCI following different TBI severities is not fully defined. This study was designed to investigate mechanistically the effects of injury severity on corticosteroid response and the development of CIRCI in a rat model of experimentally controlled TBI. Adult male Wistar rats were randomly assigned to sham, mild injury, moderate injury or severe injury groups. TBI was induced using a fluid percussion device at magnitudes of 1.2-1.4 atm (mild injury), 2.0-2.2 atm (moderate injury), and 3.2-3.5 atm (severe injury). We first assessed the effects of injury severity on the mortality and CIRCI occurrence using electrical stimulation test to assess corticosteroid response. We also investigated a series of pathological changes in the hypothalamus, especially in the paraventricular nuclei (PVN), among different injury group including: apoptosis detected by a TUNEL assay, blood-brain-barrier (BBB) permeability assessed by brain water content and Evans Blue extravasation into the cerebral parenchyma, and BBB integrity evaluated by CD31 and Claudin-5 expression and transmission electron microscopy. We made the following observations. First, 6.7% of mild-injured, 13.3% of moderate-injured, and 68.8% of severe-injured rats developed CIRCI, with a peak incidence on post-injury day 7. Second, TBI-induced CIRCI is closely correlated with injury severity. As the injury severity rises both the incidence of CIRCI and mortality surge; Third, increased level of injury severity reduces the expression of endothelial tight junction protein, aggravate BBB permeability and exacerbate the ensuing neural apoptosis in the PVN of hypothalamus. These findings indicate that increased severity of TBI aggravate the incidence of CIRCI by causing damage to tight junctions of vascular endothelial cells and increasing neuronal apoptosis in the PVN of hypothalamus.
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Fede G, Spadaro L, Tomaselli T, Privitera G, Scicali R, Vasianopoulou P, Thalassinos E, Martin N, Thomas M, Purrello F, Burroughs AK. Comparison of total cortisol, free cortisol, and surrogate markers of free cortisol in diagnosis of adrenal insufficiency in patients with stable cirrhosis. Clin Gastroenterol Hepatol 2014; 12:504-12.e8; quiz e23-4. [PMID: 23978347 DOI: 10.1016/j.cgh.2013.08.028] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Revised: 08/01/2013] [Accepted: 08/10/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Measurements of serum levels of total cortisol can overestimate the prevalence of adrenal dysfunction in patients with cirrhosis because they have low concentrations of corticosteroid-binding globulin and albumin. We used measurements of serum total cortisol and serum free cortisol after the low-dose short Synacthen test (LDSST) to assess adrenal dysfunction. METHODS We studied 79 patients with stable cirrhosis; adrenal dysfunction was defined by peak concentrations of total cortisol ≤494 mmol/L and/or peak concentrations of free cortisol ≤33 nmol/L after the LDSST. We determined free cortisol index (FCI) scores and calculated free cortisol levels by using Coolens' equation. The Cox regression model was used to assess the relationship between adrenal dysfunction and outcomes (death or liver transplant). RESULTS On the basis of measurement of total cortisol, 34% of patients had adrenal dysfunction, and on the basis of measurement of free cortisol, 29% had adrenal dysfunction. There was agreement between total cortisol and free cortisol levels in 22% of patients; in 13%, adrenal dysfunction was diagnosed only on the basis of total cortisol and in 6% only on the basis of free cortisol (κ coefficient, 0.56; P < .01). Low concentrations of corticosteroid-binding globulin (21 vs 54 μg/mL, P < .01) led to an overestimation of adrenal dysfunction that was based on measurement of total cortisol. Measurements of calculated free cortisol constantly overestimated free cortisol concentrations, with variations as large as 87% for baseline values and up to 84% after stimulation. Adrenal insufficiency, defined by FCI scores <12, was detected in 30% of patients; among them, 23% also had subnormal peak levels of free cortisol (κ coefficient, 0.70; P < .001). Adrenal dysfunction was not significantly associated with patient outcomes, on the basis of Cox model analysis. CONCLUSIONS Adrenal insufficiency, defined by LDSST, is frequent in patients with stable cirrhosis, on the basis of measurements of total and free cortisol. FCI scores are better than measurement of total cortisol in assessing adrenal function in patients with cirrhosis. We did not associate adrenal dysfunction with outcome, but further studies are needed.
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Affiliation(s)
- Giuseppe Fede
- The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, University College London and Royal Free Hospital, London, United Kingdom; 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
| | - Tania Tomaselli
- 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
| | - Roberto Scicali
- Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi Hospital, Catania, Italy
| | - Panayota Vasianopoulou
- The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, University College London and Royal Free Hospital, London, United Kingdom
| | - Evangelos Thalassinos
- The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, University College London and Royal Free Hospital, London, United Kingdom
| | - Nicholas Martin
- Department of Clinical Biochemistry, Royal Free Hospital, London, United Kingdom
| | - Michael Thomas
- Department of Clinical Biochemistry, Royal Free Hospital, London, United Kingdom
| | - 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 University Department of Surgery, University College London and Royal Free Hospital, London, United Kingdom.
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Acevedo J, Fernández J, Prado V, Silva A, Castro M, Pavesi M, Roca D, Jimenez W, Ginès P, Arroyo V. Relative adrenal insufficiency in decompensated cirrhosis: Relationship to short-term risk of severe sepsis, hepatorenal syndrome, and death. Hepatology 2013; 58:1757-1765. [PMID: 23728792 DOI: 10.1002/hep.26535] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 05/09/2013] [Accepted: 05/15/2013] [Indexed: 12/13/2022]
Abstract
UNLABELLED The prevalence of relative adrenal insufficiency (RAI) in critically ill cirrhosis patients with severe sepsis is over 60% and associated features include poor liver function, renal failure, refractory shock, and high mortality. RAI may also develop in noncritically ill cirrhosis patients but its relationship to the clinical course has not yet been assessed. The current study was performed in 143 noncritically ill cirrhosis patients admitted for acute decompensation. Within 24 hours after hospitalization adrenal function, plasma renin activity, plasma noradrenaline and vasopressin concentration, and serum levels of nitric oxide, interleukin-6 and tumor necrosis factor alpha were determined. RAI was defined as a serum total cortisol increase <9 μg/dL after 250 μg of intravenous corticotropin from basal values <35 μg/dL. Patients were followed for 3 months. RAI was detected in 26% of patients (n = 37). At baseline, patients with RAI presented with lower mean arterial pressure (76 ± 12 versus 83 ± 14 mmHg, P = 0.009) and serum sodium (131 ± 7 versus 135 ± 5 mEq/L, P = 0.007) and higher blood urea nitrogen (32 ± 24 versus 24 ± 15 mg/dl, P = 0.06), plasma renin activity (7.1 ± 9.9 versus 3.4 ± 5.6 ng/mL*h, P = 0.03), and noradrenaline concentration (544 ± 334 versus 402 ± 316 pg/mL, P = 0.02). During follow-up, patients with RAI exhibited a higher probability of infection (41% versus 21%, P = 0.008), severe sepsis (27% versus 9%, P = 0.003), type-1 hepatorenal syndrome (HRS) (16% versus 3%, P = 0.002), and death (22% versus 7%, P = 0.01). CONCLUSION RAI is frequent in noncritically ill patients with acute decompensation of cirrhosis. As compared with those with normal adrenal function, patients with RAI have greater impairment of circulatory and renal function, higher probability of severe sepsis and type-1 HRS, and higher short-term mortality.
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Affiliation(s)
- Juan Acevedo
- Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August-Pi-Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHED), Barcelona, Spain
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Chen X, Zhao Z, Chai Y, Luo L, Jiang R, Dong J, Zhang J. Stress-dose hydrocortisone reduces critical illness-related corticosteroid insufficiency associated with severe traumatic brain injury in rats. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2013; 17:R241. [PMID: 24131855 PMCID: PMC4057521 DOI: 10.1186/cc13067] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 09/17/2013] [Indexed: 12/13/2022]
Abstract
Introduction The spectrum of critical illness-related corticosteroid insufficiency (CIRCI) in severe traumatic brain injury (TBI) is not fully defined and no effective treatments for TBI-induced CIRCI are available to date. Despite growing interest in the use of stress-dose hydrocortisone as a potential therapy for CIRCI, there remains a paucity of data regarding its benefits following severe TBI. This study was designed to investigate the effects of stress-dose hydrocortisone on CIRCI development and neurological outcomes in a rat model of severe traumatic brain injury. Methods Rats were subjected to lateral fluid percussion injury of 3.2-3.5 atmosphere. These rats were then treated with either a stress-dose hydrocortisone (HC, 3 mg/kg/d for 5 days, 1.5 mg/kg on day 6, and 0.75 mg on day 7), a low-dose methylprednisolone (MP, 1 mg/kg/d for 5 days, 0.5 mg/kg on day 6, and 0.25 mg on day 7) or control saline solution intraperitoneally daily for 7 days after injury. Results We investigated the effects of stress-dose HC on the mortality, CIRCI occurrence, and neurological deficits using an electrical stimulation test to assess corticosteroid response and modified neurological severity score (mNSS). We also studied pathological changes in the hypothalamus, especially in the paraventricular nuclei (PVN), after stress-dose HC or a low dose of MP was administered, including apoptosis detected by a TUNEL assay, blood–brain barrier (BBB) permeability assessed by brain water content and Evans Blue extravasation into the cerebral parenchyma, and BBB integrity evaluated by CD31 and claudin-5 expression. We made the following observations. First, 70% injured rats developed CIRCI, with a peak incidence on post-injury day 7. The TBI-associated CIRCI was closely correlated with an increased mortality and delayed neurological recovery. Second, post-injury administration of stress-dose HC, but not MP or saline increased corticosteroid response, prevented CIRCI, reduced mortality, and improved neurological function during the first 14 days post injury dosing. Thirdly, these beneficial effects were closely related to improved vascular function by the preservation of tight junctions in surviving endothelial cells, and reduced neural apoptosis in the PVN of hypothalamus. Conclusions Our findings indicate that post-injury administration of stress-dose HC, but not MP reduces CIRCI and improves neurological recovery. These improvements are associated with reducing the damage to the tight junction of vascular endothelial cells and blocking neuronal apoptosis in the PVN of the hypothalamus.
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Trifan A, Chiriac S, Stanciu C. Update on adrenal insufficiency in patients with liver cirrhosis. World J Gastroenterol 2013; 19:445-456. [PMID: 23382623 PMCID: PMC3558568 DOI: 10.3748/wjg.v19.i4.445] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Revised: 12/03/2012] [Accepted: 12/20/2012] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is a major cause of mortality worldwide, often with severe sepsis as the terminal event. Over the last two decades, several studies have reported that in septic patients the adrenal glands respond inappropriately to stimulation, and that the treatment with corticosteroids decreases mortality in such patients. Both cirrhosis and septic shock share many hemodynamic abnormalities such as hyperdynamic circulatory failure, decreased peripheral vascular resistance, increased cardiac output, hypo-responsiveness to vasopressors, increased levels of proinflammatory cytokines [interleukine(IL)-1, IL-6, tumor necrosis factor-alpha] and it has, consequently, been reported that adrenal insufficiency (AI) is common in critically ill cirrhotic patients. AI may also be present in patients with stable cirrhosis without sepsis and in those undergoing liver transplantation. The term hepato-adrenal syndrome defines AI in patients with advanced liver disease with sepsis and/or other complications, and it suggests that it could be a feature of liver disease per se, with a different pathogenesis from that of septic shock. Relative AI is the term given to inadequate cortisol response to stress. More recently, another term is used, namely "critical illness related corticosteroid insufficiency" to define "an inadequate cellular corticosteroid activity for the severity of the patient's illness". The mechanisms of AI in liver cirrhosis are not completely understood, although decreased levels of high-density lipoprotein cholesterol and high levels of proinflammatory cytokines and circulatory endotoxin have been suggested. The prevalence of AI in cirrhotic patients varies widely according to the stage of the liver disease (compensated or decompensated, with or without sepsis), the diagnostic criteria defining AI and the methodology used. The effects of corticosteroid therapy on cirrhotic patients with septic shock and AI are controversial. This review aims to summarize the existing published information regarding AI in patients with liver cirrhosis.
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Corticosteroid replacement therapy in hepatoadrenal syndrome: case report with a review of the literature. Eur J Gastroenterol Hepatol 2012; 24:1344-7. [PMID: 22850193 DOI: 10.1097/meg.0b013e328357188c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
In liver cirrhosis, hepatoadrenal syndrome has been described recently as a progressive impairment in the adrenocortical reserve, with deficient production or action of glucocorticoids resulting in adrenal insufficiency. Data on the treatment of this syndrome are scarce. We report a case of a 60-year-old male patient referred to our hospital because of rectal bleeding and bilateral leg swelling. He complained of marked weakness, bilateral leg swelling, and shortness of breath with exertion for the last 2 months. Biochemistry and imaging indicated liver cirrhosis. Because of the weakness and persistent hypotension, we performed a low-dose synacthen test, which indicated adrenal insufficiency (baseline cortisol level 1.8 μg/dl, increasing to 3.5 and 3.7 μg/dl at 20 and 30 min, respectively). The patient's general condition improved promptly after corticosteroid supplementation.
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Theocharidou E, Krag A, Bendtsen F, Møller S, Burroughs AK. Cardiac dysfunction in cirrhosis - does adrenal function play a role? A hypothesis. Liver Int 2012; 32:1327-32. [PMID: 22292920 DOI: 10.1111/j.1478-3231.2011.02751.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Accepted: 12/20/2011] [Indexed: 12/12/2022]
Abstract
Cirrhotic cardiomyopathy (CCM), a condition of unknown pathogenesis, is characterized by suboptimal ventricular contractile response to stress, diastolic dysfunction and QT interval prolongation. It is most often found in patients with advanced cirrhosis. It is clinically relevant during stressful conditions, such as sepsis, bleeding and surgery. CCM reverses after liver transplantation and potentially has a role in the pathogenesis of hepatorenal syndrome. In adrenal insufficiency (AI), cardiac dysfunction is a feature with low ejection fraction, decreased left ventricular chamber size and electrocardiographic abnormalities, including QT interval prolongation. With optimal diagnostic tests, AI is present in approximately 10% of patients with cirrhosis, particularly in those with advanced disease. Down-regulation and decreased number of beta-adrenergic receptors, and high catecholamine levels are common to both cardiac conditions. Thus, AI may play a role in CCM. Steroid replacement therapy reverses cardiac changes in AI, and may do so for CCM, with important therapeutic implications; this needs formal evaluation.
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Affiliation(s)
- Eleni Theocharidou
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital, Royal Free Hampstead NHS Trust and UCL, London, UK
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Fede G, Spadaro L, Tomaselli T, Privitera G, Germani G, Tsochatzis E, Thomas M, Bouloux PM, Burroughs AK, Purrello F. Adrenocortical dysfunction in liver disease: a systematic review. Hepatology 2012; 55:1282-91. [PMID: 22234976 DOI: 10.1002/hep.25573] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In patients with cirrhosis, adrenal insufficiency (AI) is reported during sepsis and septic shock and is associated with increased mortality. Consequently, the term "hepato-adrenal syndrome" was proposed. Some studies have shown that AI is frequent in stable cirrhosis as well as in cirrhosis associated with decompensation other than sepsis, such as bleeding and ascites. Moreover, other studies showed a high prevalence in liver transplant recipients immediately after, or some time after, liver transplantation. The effect of corticosteroid therapy in critically ill patients with liver disease has been evaluated in some studies, but the results remain controversial. The 250-μg adreno-cortico-tropic-hormone stimulation test to diagnose AI in critically ill adult patients is recommended by an international task force. However, in liver disease, there is no consensus on the appropriate tests and normal values to assess adrenal function; thus, standardization of normal ranges and methodology is needed. Serum total cortisol assays overestimate AI in patients with cirrhosis, so that direct free cortisol measurement or its surrogates may be useful measurements to define AI, but further studies are needed to clarify this. In addition, the mechanisms by which liver disease leads to adrenal dysfunction are not sufficiently documented. This review evaluates published data regarding adrenal function in patients with liver disease, with a particular focus on the potential limitations of these studies as well as suggestions for future studies.
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Affiliation(s)
- Giuseppe Fede
- Internal Medicine, University of Catania-Garibaldi Hospital, Catania, Italy
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Thevenot T, Cervoni JP, Di Martino V. Variceal bleeding in cirrhotic patients is associated with adrenal dysfunction: what is the evidence? Clin Gastroenterol Hepatol 2012; 10:95; author reply 95. [PMID: 21888881 DOI: 10.1016/j.cgh.2011.08.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Accepted: 08/24/2011] [Indexed: 02/07/2023]
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