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Jiménez-Castillo RA, González-Martínez CE, Tovar-Bojorquez EM, Cortez-Hernández CA, Jaquez-Quintana JO, González-González JA, González-González JG, Maldonado-Garza HJ. Prognostic value of relative adrenal insufficiency in patients with severe alcohol-associated hepatitis-A prospective clinical study. GASTROENTEROLOGIA Y HEPATOLOGIA 2025; 48:502322. [PMID: 39674401 DOI: 10.1016/j.gastrohep.2024.502322] [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: 10/18/2024] [Revised: 12/04/2024] [Accepted: 12/10/2024] [Indexed: 12/16/2024]
Abstract
BACKGROUND/AIMS Relative adrenal insufficiency (RAI) is frequent in patients with liver cirrhosis and affects their prognosis. Scarce data on RAI in patients with alcohol-associated hepatitis (AAH) exists. This study aimed to document the prevalence and prognostic implication of RAI in patients with severe AAH. PATIENTS AND METHODS Adults with a first episode of AAH were selected. The delta cortisol level was the difference between the serum basal cortisol and 60min after ACTH stimulation. Cox proportional-hazard regression model was used for univariate analysis of prognostic factors with 95% confidence intervals. The Kaplan-Meier and log-rank tests were applied for survival analysis between patients with RAI and without RAI. RESULTS Twenty-five subjects with a first episode of AAH were included. Eight (32.0%) deaths occurred in our cohort. Univariate analysis showed that presence of RAI (p=0.049) had a significant impact on 90-day Overall Survival (OS). Serum albumin (p=0.991), serum creatinine (p=0.954), sodium (p=0.986) and international normalized ratio (p=0.073) did not show a significant impact on 90-day OS. Ninety-day overall survival for patients with RAI was 50.0% vs. 90.9% in those without RAI, (p=0.040). CONCLUSIONS The presence of RAI seems to be a fair predictor of intermediate-term survival in AAH patients.
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Affiliation(s)
- Raúl Alberto Jiménez-Castillo
- Gastroenterology Department, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - Carlos Eugenio González-Martínez
- Gastroenterology Department, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - Elianee María Tovar-Bojorquez
- Gastroenterology Department, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - Carlos Alejandro Cortez-Hernández
- Gastroenterology Department, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Monterrey, Mexico.
| | - Joel Omar Jaquez-Quintana
- Gastroenterology Department, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - José Alberto González-González
- Gastroenterology Department, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - José Gerardo González-González
- Plataforma INVEST Medicina UANL, KER Unit Mayo Clinic (KER Unit Mexico), Universidad Autónoma de Nuevo León, Monterrey, Mexico; Endocrinology Division, Department of Internal Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - Héctor Jesús Maldonado-Garza
- Gastroenterology Department, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Monterrey, Mexico
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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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3
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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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Cohen EA, Moeller CM, Dear JD. Hypoadrenocorticism in a Dog Following Recovery from Alpha-Amanitin Intoxication. Vet Sci 2023; 10:500. [PMID: 37624287 PMCID: PMC10459733 DOI: 10.3390/vetsci10080500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/27/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open
Abstract
A 10-year-old, female spayed Labrador Retriever was referred for acute hepatopathy and urinary retention. Blood work from the initial presentation (day 0) revealed a severe, mixed hepatopathy. Over the course of the patient's hospitalization, the patient developed liver insufficiency. Urine was submitted for toxicological screening and revealed detection of a trace concentration of alpha-amanitin. The patient was treated supportively for alpha-amanitin intoxication and was discharged from the hospital on day 8, with most biochemical parameters being markedly improved. The patient was persistently hyporexic at the time of discharge. On day 15, at a recheck appointment, the patient had lost 2.4 kg and liver enzymology revealed improved values. On day 24, the patient was presented for anorexia and vomiting and had lost another 2.3 kg. Blood work and endocrinological testing at that time were consistent with hypoadrenocorticism. The patient was started on glucocorticoids and mineralocorticoids. At day 106, the patient was doing well clinically while receiving monthly mineralocorticoids and daily glucocorticoids. This case report is the first to describe the chronological association between alpha-amanitin-induced liver dysfunction and the subsequent development of adrenal insufficiency in a dog.
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Affiliation(s)
- Emily A. Cohen
- William Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, CA 95616, USA; (E.A.C.); (C.M.M.)
| | - Courtney M. Moeller
- William Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, CA 95616, USA; (E.A.C.); (C.M.M.)
| | - Jonathan D. Dear
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, CA 95616, USA
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5
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Ekawaravong S, Treepongkaruna S, Poomthavorn P, Pongratanakul S, Khlairit P, Chanprasertyothin S, Mahachoklertwattana P. Overdiagnosis of adrenal insufficiency in children with biliary atresia. Clin Pediatr Endocrinol 2023; 32:147-154. [PMID: 37362167 PMCID: PMC10288293 DOI: 10.1297/cpe.2022-0083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 04/03/2023] [Indexed: 06/28/2023] Open
Abstract
Serum cortisol mainly binds to the cortisol-binding globulin (CBG). Children with biliary atresia (BA) may have low serum CBG levels; thus, low serum total cortisol (TC) levels and adrenal insufficiency (AI) may be overdiagnosed. This study aimed to assess adrenal function in children with BA. All the patients underwent adrenocorticotropic hormone (ACTH) stimulation tests. Plasma ACTH, serum TC, and CBG levels were measured at baseline, with additional TC measurements at 30 and 60 min during testing. Free cortisol (FC) index (FCI) and calculated FC (cFC) were also calculated. AI was defined as peak TC <500 nmol/L (<18 μg/dL), peak FCI <12 nmol/mg, or peak cFC <33 nmol/L (<1.2 μg/dL). This study enrolled 71 children with BA. The Median (IQR) age of the patients was 5.5 (1.7-11.4) years. Twenty-five (35%) patients were diagnosed with AI based on the peak TC. In the AI group, the median serum CBG level was significantly lower than that in the non-AI group (481 vs. 533 nmol/L, p = 0.03). Only eight patients (11%) met all three AI criteria (six secondary AI and two primary AI). In conclusion, low serum CBG levels contribute to reduced peak TC and, consequently, overdiagnosing AI. Peak FCI and cFC could help reduce the overdiagnosis of AI.
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Affiliation(s)
- Suparat Ekawaravong
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Suporn Treepongkaruna
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Preamrudee Poomthavorn
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sarunyu Pongratanakul
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Patcharin Khlairit
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Pat Mahachoklertwattana
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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6
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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
Patients with cirrhosis frequently require admission to the intensive care unit as complications arise in the course of their disease. These admissions are associated with high short- and long-term morbidity and mortality. Thus, understanding and characterizing complications and unique needs of patients with cirrhosis and acute-on-chronic liver failure helps providers identify appropriate level of care and evidence-based treatments. While there is no widely accepted critical care admission criteria for patients with cirrhosis, the presence of organ failure and primary or nosocomial infections are associated with particularly high in-hospital mortality. Optimal management of patients with cirrhosis in the critical care setting requires a system-based approach that acknowledges deviations from canonical pathophysiology. In this review, we discuss appropriate considerations and evidence-based practices for the general care of patients with cirrhosis and critical illness.
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Affiliation(s)
- Thomas N Smith
- Department of Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota
| | - Alice Gallo de Moraes
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic Rochester, Rochester, Minnesota
| | - Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, Minnesota
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8
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He X, Wu J, Hou W, Li J, Xu H. Association of hydroxysteroid 11-beta dehydrogenase 1 polymorphisms with chronic liver fibrosis and the occurrence of hepatocellular carcinoma in a Han Chinese population. ALL LIFE 2022. [DOI: 10.1080/26895293.2021.2000893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
Affiliation(s)
- Xiuting He
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, People’s Republic of China
| | - Jing Wu
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, People’s Republic of China
| | - Wenli Hou
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, People’s Republic of China
| | - Jie Li
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, People’s Republic of China
| | - Hongqin Xu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, People’s Republic of China
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9
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Kim Y, Koh JS, Woo SD, Lee SI, Kang DH, Park D, Chung C, Kwon IS, Lee JE. The Tri-iodothyronine (T3) Level Is a Prognostic Factor for Patients With Advanced NSCLC: Receiving Immune Checkpoint Inhibitors and Is Associated With Liver Metastasis. Clin Med Insights Oncol 2022; 16:11795549221139522. [PMID: 36532699 PMCID: PMC9751177 DOI: 10.1177/11795549221139522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 11/01/2022] [Indexed: 08/22/2023] Open
Abstract
BACKGROUND Endocrine hormones influence tumor progression and the response to treatment. Despite the importance of immune checkpoint inhibitors (ICIs) as treatments for advanced non-small cell lung cancer (NSCLC), few studies have explored the effects of hormone levels in NSCLC patients on the effectiveness of ICI therapies. We thus investigated the effects of baseline blood markers in patients with advanced NSCLC on ICI treatments. METHODS Patients with advanced NSCLC who received programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors at Chungnam National University Hospital between December 2016 and November 2020 and who lacked any history of thyroid gland-related diseases were analyzed retrospectively. We collected clinical information and baseline laboratory data, including the levels of endocrine hormones, cytokines, complete blood counts (CBCs), and peripheral blood chemistry panels. We explored the relationships of hormone levels with clinical outcomes (overall survival [OS], progression-free survival [PFS], and best response), liver metastasis, and blood markers using the Kaplan-Meier method, Cox's proportional hazards regression, and logistic regression. RESULTS A total of 113 patients were enrolled. A shorter PFS was independently associated with liver metastasis, higher cortisol levels, and lower hemoglobin (Hb) levels; a shorter OS was associated with liver metastasis, lower tri-iodothyronine (T3) levels, higher lactate dehydrogenase (LDH) levels, and lower albumin levels. Patients with low T3 levels exhibited a shorter PFS and OS, and a poorer best response. Patients with low T3 levels tended to have higher disease progression rates, lower levels of adrenocorticotropic hormone (ACTH), C-peptide, albumin, Hb, and neutrophil-to-lymphocyte ratio, and higher levels of interleukin (IL)-6, white blood cells, platelets, compared with those with normal T3 levels. We found a significant association between a low T3 level and liver metastasis. CONCLUSIONS We found the baseline T3 level was associated with both prognosis and the response to ICIs in patients with advanced NSCLC, probably reflecting impaired liver function and systemic inflammation induced by the interaction of T3 with other biomarkers, such as IL-6, ACTH, cortisol, C-peptide, Hb, LDH, and albumin.
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Affiliation(s)
- Yoonjoo Kim
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Jeong Suk Koh
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Seong-Dae Woo
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Song-I Lee
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Da Hyun Kang
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Dongil Park
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Chaeuk Chung
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - In-Sun Kwon
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Jeong Eun Lee
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
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10
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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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11
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Kaur B, Cardenas A, Karvellas CJ. Pretransplant management of the patient with severe acute-on-chronic liver failure. Clin Liver Dis (Hoboken) 2022; 19:187-190. [PMID: 35662868 PMCID: PMC9135152 DOI: 10.1002/cld.1222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 02/11/2022] [Accepted: 02/23/2022] [Indexed: 02/04/2023] Open
Affiliation(s)
- Bhupinder Kaur
- Internal Medicine DepartmentCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | | | - Constantine J. Karvellas
- Division of Critical Care MedicineUniversity of AlbertaEdmontonAlbertaCanada,Division of Gastroenterology, Faculty of Medicine and DentistryUniversity of AlbertaEdmontonAlbertaCanada
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12
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Abstract
Hepatorenal syndrome (HRS) is defined as a functional renal failure without major histologic changes in individuals with severe liver disease and it is associated with a high mortality rate. Renal hypoperfusion due to marked vasoconstriction as a result of complex circulatory dysfunction has been suggested to be the cornerstone of HRS. Splanchnic and peripheral arterial vasodilation and cirrhotic cardiomyopathy result in effective arterial hypovolemia and compensatory activation of vasoconstrictor mechanisms. The efficacy of current therapeutic strategies targeting this circulatory dysfunction is limited. Increasing evidence suggests a substantial role of systemic inflammation in HRS via either vascular or direct renal effects. Here we summarize the current understanding of HRS pathophysiology.
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Affiliation(s)
- Timea Csak
- Sandra Atlas Bass Center for Liver Diseases, Northwell Health, 400 Community Drive, Manhasset, NY 11030, USA.
| | - David Bernstein
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Zucker School of Medicine at Hofstra/Northwell, 400 Community Drive, Manhasset, NY 11030, USA
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13
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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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Singh S, Taneja S, Tandon P, De A, Verma N, Premkumar M, Duseja A, Dhiman RK, Singh V. High Prevalence of Hormonal Changes and Hepatic Osteodystrophy in Frail Patients with Cirrhosis-An Observational Study. J Clin Exp Hepatol 2022; 12:800-807. [PMID: 35677501 PMCID: PMC9168697 DOI: 10.1016/j.jceh.2021.11.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 11/20/2021] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND/AIM Hormonal changes and hepatic osteodystrophy are less often studied complications of cirrhosis. This study describes the variance in hormones and osteodystrophy between Frail and Not frail patients with cirrhosis. METHODS 116 outpatients with cirrhosis were prospectively enrolled in this study. Frailty assessment was done using Liver Frailty Index (LFI). Sociodemographic assessment, anthropometry, nutritional assessment, hormone profile, and dual-energy X-ray absorptiometry scan were done in all patients. RESULTS 116 patients, predominantly males (100 (86.2%) with mean age of 50.16 years (95% CI, 48.43-51.89) were included. Malnutrition was more common in Frail group as compared to Not frail group. Subjective global assessment (SGA) class-B patients were significantly more in Frail group (37 (74%) vs 3 (4.5%), P = 0.001). The prevalence of lower parathyroid hormone (PTH) (14 (28%) vs 2 (3%)), testosterone (33 (66%) vs 15 (22.7%)), vitamin D3 (44 (88%) vs 39 (59.1%)), and cortisol (37 (74%) vs 37 (56.1) levels was higher in Frail group (P < 0.05). The number of patients diagnosed with osteodystrophy (34 (68%) vs 21 (31.8%), P = 0.001) was significantly higher in Frail group. The marker of osteoclastic activity, β-cross laps, was significantly elevated in the Frail group both in males (736 (655-818) vs 380 (329-432), P = 0.001) and (females 619 (479-758) vs 313 (83-543), P = 0.02). Bone mineral density (BMD) at lumbar spine (LS) and neck of femur (NF) had significant correlation with LFI (ρ = 0.60, P = 0.001 for LS and ρ = 0.59, P = 0.001 for NF), serum testosterone (ρ = 0.58, P = 0.001 for LS and ρ = 0.53, P = 0.001 for NF), β-cross laps (ρ = 0.38, P = 0.001for LS and ρ = 0.35, P = 0.000 for NF), vitamin D3 (ρ = 0.23, P = 0.04 for LS and ρ = 0.25, P = 0.01 for NF), PTH (ρ = 0.52, P = 0.001 for LS and ρ = 0.48. P = 0.001 for NF), and cortisol (ρ = 0.50, P = 0.001 for LS and ρ = 0.45, P = 0.001 for NF) levels. CONCLUSION This is the first study that highlights the high prevalence of hormonal changes and hepatic osteodystrophy in frail patients with cirrhosis and opens a new dimension for research and target of therapy in this field.
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Key Words
- ANOVA, analysis of variance
- BMD, bone mineral density
- BMI, body mass index
- CI, confidence interval
- CRP, C-reactive protein
- CTP, Child–Turcotte–Pugh
- DEXA, dual-energy X-ray absorptiometry
- ESR, erythrocyte sedimentation rate
- HCC, hepatocellular carcinoma
- HE, hepatic encephalopathy
- IBM, International Business Machines
- LFI, Liver Frailty Index
- MAC, mid-arm circumference
- MAMC, mid-arm muscle circumference
- MELD, model for end-stage liver disease
- MELDNa, model for end-stage liver disease with sodium
- NASH, non-alcoholic steatohepatitis
- P1-NP, procollagen type 1 N-terminal propeptide
- PTH, parathyroid Hormone
- SGA, subjective global assessment
- SPSS, Statistical Package for Social Sciences
- T3, triiodothyronine
- T4, tetraiodothyronine
- TIBC, total iron-binding capacity
- TSF, triceps skin-fold thickness
- TSH, thyroid stimulating hormone
- cirrhosis
- frailty
- hormonal changes
- osteodystrophy
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Affiliation(s)
- Surender Singh
- Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Sunil Taneja
- Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh, India,Address for correspondence: Dr. Sunil Taneja, Associate Professor, Department of Hepatology, PGIMER, Chandigarh, India. Tel.: +919592160444.
| | - Puneeta Tandon
- Division of Gastroenterology, University of Alberta, Edmonton, Canada
| | - Arka De
- Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Nipun Verma
- Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Radha Krishan Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Virendra Singh
- Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
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Theiler-Schwetz V, Schlager H, Obermayer-Pietsch B, Stojakovic T, Fauler G, Fickert P, Zollner G. Hypercortisolism in patients with cholestasis is associated with disease severity. BMC Gastroenterol 2021; 21:460. [PMID: 34876016 PMCID: PMC8650422 DOI: 10.1186/s12876-021-02045-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 11/24/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Cholestasis might lead to an impairment of adrenal function as suggested by in vitro and in vivo data as well as by clinical findings. Bile acid and adrenal steroid metabolism not only share the receptors farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (TGR5), but supraphysiological bile acid levels were found to stimulate steroidogenesis independent of FXR and TGR5. Our previous experimental findings revealed that mice fed bile acids or subjected to common bile duct ligation develop hypercortisolemia. We thus aimed to assess adrenal gland function in patients with cholestasis. METHODS Adrenal gland function was assessed in 36 patients with cholestasis and in 32 patients without cholestasis by measuring total serum cortisol, adrenocorticotropic hormone (ACTH), as well as the increase of cortisol 20 and 30 min after administration of 1 µg of ACTH. Bile acid levels and bile acid pool composition were determined by high-resolution mass spectrometry. RESULTS Patients with cholestasis per definition had markedly elevated levels of alkaline phosphatase (AP), bilirubin and serum bile acids. Baseline cortisol and maximum cortisol after ACTH stimulation were significantly higher in patients with cholestasis compared to controls. Increase of cortisol after ACTH stimulation and ACTH did not differ. In the cholestasis group, baseline cortisol correlated with bilirubin but not with AP, total serum bile acids and levels of conjugated and unconjugated bile acid species. Patients with duration of cholestasis < 6 months (n = 30) had significantly higher baseline cortisol levels than those with long standing cholestasis (> 6 months), together with higher bilirubin levels. CONCLUSIONS We find no evidence of adrenal insufficiency in non-cirrhotic patients with cholestasis. In contrast, patients with cholestasis show hypercortisolism associated with disease severity as mirrored by levels of bilirubin. Lack of ACTH increase in cholestasis suggests a direct effect of cholestasis on adrenals and not on the pituitary gland. Further studies are needed to elucidate the mechanism of cortisol elevation in patients with cholestasis and its clinical significance.
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Affiliation(s)
- Verena Theiler-Schwetz
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, University Hospital Graz, Graz, Austria
| | - Hansjörg Schlager
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, University Hospital Graz, Graz, Austria
| | - Barbara Obermayer-Pietsch
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, University Hospital Graz, Graz, Austria
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Graz, Austria
| | - Günter Fauler
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Graz, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, University Hospital Graz, Graz, Austria
| | - Gernot Zollner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, University Hospital Graz, Graz, Austria.
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Piccolo Serafim L, Simonetto DA, Anderson AL, Choi DH, Weister TJ, Hanson AC, Kamath PS, Gajic O, Gallo de Moraes A. Clinical Effect of Systemic Steroids in Patients with Cirrhosis and Septic Shock. Shock 2021; 56:916-920. [PMID: 34132218 DOI: 10.1097/shk.0000000000001822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE Evidence regarding the utility of systemic steroids in treating patients with cirrhosis and septic shock remains equivocal. This study aimed to evaluate and elucidate the association of steroid use with outcomes and adverse effects in a cohort of patients with cirrhosis and septic shock. PATIENTS AND METHODS Retrospective cohort study of patients with cirrhosis and septic shock admitted to a tertiary hospital intensive care unit (ICU) from January 2007 to May 2017, using a validated ICU Datamart. Patients who received vasopressors within 6 h of ICU admission were included in the multivariate analysis. The effect of steroids on outcomes was evaluated using multivariable regression, adjusting for confounding variables. RESULTS Out of 179 admissions of patients with cirrhosis and septic shock, 56 received steroids during the ICU admission. Patients who received steroids received a higher total dose of vasopressors (91.2 mg vs. 39.1 mg, P = 0.04) and had a lower initial lactate level (1.8 mmol/L vs. 2.6 mmol/L, P = 0.007). The multivariate analysis included 117 patients and showed no significant differences in mortality, length of ICU admission, or length of hospital stay. Bleeding events, delirium, and renal-replacement therapy requirements were also not associated with the use of steroids. CONCLUSION The use of systemic steroids was more prevalent in cirrhotic patients with higher vasopressor requirements. It was not associated with decreased mortality or increased ICU- and hospital-free days, or to adverse effects.
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Affiliation(s)
- Laura Piccolo Serafim
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
- Multidisciplinary Epidemiology and Translational Research in Intensive Care (METRIC) Group, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Alexandra L Anderson
- Division of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Dae Hee Choi
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
- Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon-si, Gangwon-do, Republic of Korea
| | - Timothy J Weister
- Division of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Andrew C Hanson
- Multidisciplinary Epidemiology and Translational Research in Intensive Care (METRIC) Group, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
- Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Ognjen Gajic
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
- Multidisciplinary Epidemiology and Translational Research in Intensive Care (METRIC) Group, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Alice Gallo de Moraes
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
- Multidisciplinary Epidemiology and Translational Research in Intensive Care (METRIC) Group, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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Assessment of adrenal response in patients with stable cirrhosis and ascites using different short Synacthen tests and definitions. Eur J Gastroenterol Hepatol 2021; 33:e540-e547. [PMID: 33905212 DOI: 10.1097/meg.0000000000002153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIMS The definition of relative adrenal insufficiency (RAI) in patients with cirrhosis remains controversial. We investigated the serum and salivary cortisol (SalC) response after low-dose and standard-dose Synacthen test in patients with stable cirrhosis and ascites. METHODS Ninety-five cirrhotic patients with ascites were prospectively evaluated from January 2014 to January 2018. Low-dose [adrenocorticotrophic hormone (ACTH): 1 μg] and standard-dose (ACTH: 250 μg) Synacthen test were successively performed. Paired serum total and saliva cortisol were taken at baseline, 30 min (low-dose test) and 60 min (standard-dose test). Salivary and Δserum total cortisol criteria included post-ACTH SalC < 12.7 ng/ml and/or SalC increase <3 ng/ml and serum total cortisol increase <9 μg/dl, respectively. RESULTS The prevalence of RAI varied according to the definition used. SalC-defined RAI was significantly more common after low-dose than standard-dose test (54.7% vs. 20%; P < 0.001). Δserum total cortisol-defined RAI was also significantly more frequent after low-dose than standard-dose test (66.3% vs. 24.2%; P < 0.001). Considering low-dose test/SalC criteria as reference diagnostic criteria, standard-dose/salivary and Δserum total cortisol criteria showed low specificity for RAI diagnosis (43.9% and 52.7%, respectively). Survival probability was significantly lower in patients with low-dose test/SalC-defined RAI compared to those without (53.8% vs. 79.1%; P = 0.01). SalC-defined RAI after low-dose test was significantly more common than that defined after standard-dose test (72.7% vs. 30.3%; P < 0.001) among patients who died. CONCLUSION Low-dose test/SalC definition can identify RAI in about half of patients with stable cirrhosis and ascites and is associated with increased mortality.
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Nso N, Nassar M, Baraka B, Mbome Y, Alfishawy M. Adrenal Insufficiency in patients with cardiogenic shock: A meta-analysis. Diabetes Metab Syndr 2021; 15:102274. [PMID: 34628137 DOI: 10.1016/j.dsx.2021.102274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 08/30/2021] [Accepted: 09/01/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Adrenal Insufficiency (AI) is rarely observed in patients with cardiogenic shock (CS). We aimed to identify the prevalence of AI in patients with CS and its effect on their clinical outcomes. AIMS Our study aimed to determine the prevalence of AI in CS patients who underwent treatments for CS. METHODS The articles concerning AI in CS were extracted for review from PubMed/Medline, Science Direct, World Wide Science.org, and Pro-Quest. The research articles included patients with CS, post-cardiac-arrest shock, out-of-hospital cardiac arrest, and CS after acute myocardial infarction. RStudio (version 1.0.136) was used for analyzing AI in CS patients. RESULTS The search revealed 1463 unique publications, including 256 studies identified after screening the titles and the abstracts. Five observational cohort studies met the eligibility criteria for meta-analysis after the preliminary screening. The included studies reported a corticotropin stimulation test for AI diagnosis. The studies reportedly exhibited a low-to-fair quality. The random-effects pooled estimates indicated a 32% AI prevalence in the setting of CS [95% CI; 21%-45%; I2 = 81%]. The outcomes from the included studies were statistically significant for high heterogeneity (P = 0.001). The pooled results confirmed an 11%-51% AI prevalence in CS patients. CONCLUSIONS This meta-analysis revealed a moderate level prevalence of AI in CS patients.
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Affiliation(s)
- Nso Nso
- Internal Medicine Department, Icahn School of Medicine at Mount Sinai / NYC Health+Hospitals / Queens, New York, NY, USA.
| | - Mahmoud Nassar
- Internal Medicine Department, Icahn School of Medicine at Mount Sinai / NYC Health+Hospitals / Queens, New York, NY, USA.
| | - Bahaaeldin Baraka
- Clinical Oncology Department, Nottingham University Hospital, Nottingham, UK.
| | - Yolanda Mbome
- Internal Medicine Department, Richmond University Medical Center, New York, USA.
| | - Mostafa Alfishawy
- Infectious Diseases, Infectious Diseases Consultants and Academic Researchers of Egypt (IDCARE), Cairo, Egypt.
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Siramolpiwat S, Kerdsuknirun J, Tharavanij T. An impact of relative adrenal insufficiency on short-term outcomes in non-critically ill cirrhotic patients: A prospective cohort study. Int J Clin Pract 2021; 75:e14362. [PMID: 33993598 DOI: 10.1111/ijcp.14362] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 05/09/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Relative adrenal insufficiency (RAI) is frequently found in patients with liver cirrhosis, especially in critically ill conditions. However, the prognostic impact of RAI in non-critically ill cirrhosis remains controversial. The aim of the present study was to assess the prevalence of RAI and its prognostic implication in non-critically ill cirrhotic patients. METHODS From December 2015 to November 2017, hospitalised non-critically ill cirrhotic patients admitted with hepatic decompensation were prospectively enrolled in this study. Within 24 hours after admission, 250 mcg ACTH stimulation test was performed. RAI was defined as an increase in serum cortisol <9 mcg/dL in patients with basal serum cortisol <35 mcg/dL. Clinical outcomes were evaluated during admission and at 30-, 90-day visits. RESULTS One hundred and fifteen patients were included (66% male, mean age 59.9 ± 16 years, mean MELD 16.1 ± 6.8, Child A/B/C 15.7%/53.9%/30.4%). The main indications for admission were bacterial infection (44.6%) and portal hypertension-related bleeding (19.1%). RAI was detected in 35 patients (30.4%). Patients with RAI had higher Child-Pugh score (9.4 ± 1.9 vs 8.0 ± 1.7, P < .01), and MELD scores (18.3 ± 5.9 vs 15.1 ± 6.9, P = .02). The in-hospital, 30-, and 90-day mortality rates were 9.6%, 20.9%, and 26.1%, respectively. There was no significant difference in the incidence of nosocomial infection, severe sepsis, septic shock, HRS, and mortality rates between patients with and without RAI. By multivariate analysis, bacterial infection on admission (HR 3.13, P < .01) and acute-on-chronic liver failure (HR 4.98, P < .001) were independent predictors of 90-day survival. CONCLUSIONS RAI is found in about one-third of hospitalised non-critically ill cirrhotic patients and is associated with the severity of cirrhosis. However, the presence of RAI has no influence on short-term outcomes.
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Affiliation(s)
- Sith Siramolpiwat
- Department of Medicine, Chulabhorn International College of Medicine (CICM), Thammasat University, Pathumthani, Thailand
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Jitrapa Kerdsuknirun
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Thipaporn Tharavanij
- Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
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Zhang J, Li J, Chen Y, Ding M, Duan Z. Prognostic Factors Related to the Mortality Rate of Acute-on-Chronic Liver Failure Patients. Diabetes Metab Syndr Obes 2021; 14:2573-2580. [PMID: 34135609 PMCID: PMC8200164 DOI: 10.2147/dmso.s309641] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/21/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Critical illness-related corticosteroid insufficiency (CIRCI) is known to be a common complication in patients with acute-on-chronic liver failure (ACLF). However, factors that predict the survival rate of ACLF patients remain unclear. The present study aims to determine the prognostic factors that impinge on the survival rate of ACLF patients. METHODS A total of 90 patients with ACLF at different stages, with or without CIRCI, were prospectively evaluated. RESULTS Various clinical factors were found to be significantly different among patients at early, mid and late stages of ACLF, as well as between the same population of patients with and without CIRCI. Specifically, patients at later stages of ACLF and patients with CIRCI had significantly higher Child-Turcotte-Pugh (CTP), Model for End-Stage Liver Disease (MELD) and ACLF Research Consortium (AARC)-ACLF scores. CIRCI was observed in 20% of the enrolled patients (18 out of 90). In addition, the 90-day mortality rate was higher in mid- and late-stage ACLF patients, as well as patients with CIRCI. CONCLUSION ACLF stage and CIRCI predict early mortality in patients with ACLF and could be actively monitored in these patients for prioritized liver transplantation.
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Affiliation(s)
- Jian Zhang
- Difficult & Complicated Liver diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, People’s Republic of China
| | - Junfeng Li
- The First Hospital of Lanzhou University, Department of Infectious Diseases, Lanzhou, People’s Republic of China
| | - Yu Chen
- Difficult & Complicated Liver diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, People’s Republic of China
| | - Mei Ding
- Difficult & Complicated Liver diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, People’s Republic of China
| | - Zhongping Duan
- Difficult & Complicated Liver diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, People’s Republic of China
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Lovato CM, Thévenot T, Borot S, Di Martino V, Qualls CR, Urban FK, Dorin RI. Decreased maximal cortisol secretion rate in patients with cirrhosis: Relation to disease severity. JHEP Rep 2021; 3:100277. [PMID: 34027338 PMCID: PMC8121968 DOI: 10.1016/j.jhepr.2021.100277] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 02/13/2021] [Accepted: 03/07/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND & AIMS Hepatic enzymes play a major role in the metabolic elimination of cortisol, and reduced rates of cortisol clearance have been consistently observed in patients with chronic liver disease. It is less clear whether there are concomitant abnormalities of adrenocortical function in patients with cirrhosis. In the present study, we sought to assess adrenocortical function in patients with cirrhosis using measures of free cortisol appearance and elimination rates that are independent of serum concentrations of cortisol binding proteins. METHODS Post hoc analysis used computer-assisted numerical and modelling methods with serial total and free cortisol concentration data to obtain rates of free cortisol appearance and elimination. Rate parameters were obtained in 114 patients with chronic liver disease, including Child-Pugh (CP) ≤8 (n = 53) and CP >8 (n = 61). RESULTS Maximal cortisol secretion rate (CSRmax) was significantly decreased (p = 0.01) in patients with cirrhosis with CP >8 (0.28 nM/s; 95% CI 0.24-0.34) compared with those with CP ≤8 (0.39 nM/s; 95% CI 0.33-0.46), and CSRmax was negatively correlated with CP score (r = -0.19, p = 0.01). Free cortisol elimination rate was significantly (p = 0.04) decreased in the CP >8 group (0.16 ± 0.20 min-1) compared with that in the CP ≤8 group (0.21 ± 0.21 min-1), and free cortisol elimination rates were negatively correlated with CP score (r = -0.23, p = 0.01). A significant correlation between CSRmax and free cortisol elimination rate (r = 0.88, p <0.001) was observed. CONCLUSIONS CSRmax and free cortisol elimination rates were significantly reduced according to severity of cirrhosis. In contrast to stimulated total cortisol concentrations, CSRmax estimates were independent of cortisol-binding protein concentrations. Results provide additional evidence of subnormal adrenocortical function in patients with cirrhosis. LAY SUMMARY We applied numerical analytic methods to characterise adrenocortical function in patients with varying stages of chronic liver disease. We found that patients with more severe cirrhosis have decreased rate of free cortisol elimination and decreased maximal cortisol secretion rate, which is a measure of adrenocortical function. In contrast to conventional measures of adrenocortical function, those obtained using numerical methods were not affected by variation in corticosteroid binding globulin and albumin concentrations. We conclude that patients with cirrhosis demonstrate measurable abnormalities of adrenocortical function, evidence of which supports aspects of the hepatoadrenal syndrome hypothesis.
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Key Words
- ACLF, acute-on-chronic liver failure
- ACTH, adrenocorticotrophin
- AI, adrenal insufficiency
- Adrenal insufficiency
- CBG, corticosteroid-binding globulin
- CIRCI, critical illness-related corticosteroid insufficiency
- CP, Child-Pugh
- CPR, cortisol production rate
- CRP, C-reactive protein
- CRT, corticosteroid replacement therapy
- CSR, cortisol secretion rate
- CSRbase, basal CSR (before ACTH stimulation)
- CSRmax, maximal CSR
- Computer-assisted numerical analysis
- HPA, hypothalamic–pituitary–adrenal
- HSD, hydroxysteroid dehydrogenase
- Hydrocortisone
- INR, international normalised ratio
- Liver disease
- MCR, metabolic clearance rate
- MELD, model for end-stage liver disease
- Metabolic clearance rate
- PAI, primary adrenal insufficiency
- RAI, relative adrenal insufficiency
- RCT, randomised clinical trial
- SAI, secondary adrenal insufficiency
- SCOTCH, Supplemental Corticosteroids in Cirrhotic Hypotensive Patients With Suspicion of Sepsis
- STB, standardised beta
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Affiliation(s)
- Christina M. Lovato
- Department of Internal Medicine/Endocrinology, Diabetes and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Thierry Thévenot
- Service d’Hépatologie et de Soins Intensifs Digestifs, Hôpital Universitaire Jean Minjoz, Besançon, France
| | - Sophie Borot
- Service d’Endocrinologie-Métabolisme et Diabétologie-Nutrition, Hôpital Jean Minjoz, Besançon, France
| | - Vincent Di Martino
- Service d’Hépatologie et de Soins Intensifs Digestifs, Hôpital Universitaire Jean Minjoz, Besançon, France
| | - Clifford R. Qualls
- Department of Mathematics and Statistics, University of New Mexico, Albuquerque, NM, USA
- New Mexico Veterans Affairs Healthcare System, Albuquerque, NM, USA
| | - Frank K. Urban
- Department of Electrical and Computer Engineering, Florida International University, Miami, FL, USA
| | - Richard I. Dorin
- Department of Internal Medicine/Endocrinology, Diabetes and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
- New Mexico Veterans Affairs Healthcare System, Albuquerque, NM, USA
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22
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Kalra S, Bhattacharya S, Rawal P. Hepatocrinology. Med Sci (Basel) 2021; 9:39. [PMID: 34205986 PMCID: PMC8293374 DOI: 10.3390/medsci9020039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/10/2021] [Accepted: 05/24/2021] [Indexed: 11/17/2022] Open
Abstract
Hepatocrinology is defined as a bidirectional, complex relationship between hepatic physiology and endocrine function, hepatic disease and endocrine dysfunction, hepatotropic drugs and endocrine function, and endocrine drugs and hepatic health. The scope of hepatocrinology includes conditions of varied etiology (metabolic, infectious, autoimmune, and invasive) that we term as hepato-endocrine syndromes. This perspective shares the definition, concept, and scope of hepatocrinology and shares insight related to this aspect of medicine. It is hoped that this communication will encourage further attention and research in this critical field.
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Affiliation(s)
- Sanjay Kalra
- Department of Endocrinology, Bharti Hospital, Karnal 132001, India
| | | | - Pawan Rawal
- Department of Gastroenterology, Artemis Hospital, Gurgaon 122002, India;
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23
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Piano S, Favaretto E, Tonon M, Antonelli G, Brocca A, Sticca A, Mareso S, Gringeri E, Scaroni C, Plebani M, Russo FP, Burra P, Cillo U, Angeli P. Including Relative Adrenal Insufficiency in Definition and Classification of Acute-on-Chronic Liver Failure. Clin Gastroenterol Hepatol 2020; 18:1188-1196.e3. [PMID: 31589973 DOI: 10.1016/j.cgh.2019.09.035] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 09/14/2019] [Accepted: 09/26/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Relative adrenal insufficiency (RAI) is defined by insufficient production of cortisol relative to organ demand. RAI is observed frequently in hospitalized patients with cirrhosis, but there is disagreement over the clinical effects of RAI in these patients. We evaluated the prevalence and the clinical effects of RAI in hospitalized patients with cirrhosis. METHODS We performed a prospective study of 160 patients admitted to a hospital in Italy for acute decompensation of cirrhosis from May 2011 through September 2016. Patients were followed up until death, liver transplantation, or a maximum of 90 days. Serum and salivary levels of cortisol were measured before and after a 1-hour Short Synacthen Test. A diagnosis of RAI was given to patients with an increase in serum cortisol of less than 9 μg/dL, after Synacthen administration, in patients with baseline serum levels of cortisol less than 35 μg/dL. We collected blood samples before the Synacthen test and analyzed them for blood cell counts, liver and renal function, levels of C-reactive protein, and lipid profiles (total cholesterol, high-density lipoprotein cholesterol, apolipoprotein-A1). RESULTS A diagnosis of RAI was made for 78 patients (49%). Age (odds ratio [OR], 0.95; P = .030), number of leukocytes (OR, 3.10; P = .006), and levels of high-density lipoprotein cholesterol (OR, 0.30; P = .039) were associated independently with RAI. Patients with RAI had a significantly higher risk of developing bacterial infections (hazard ratio [HR], 1.60; P = .038), sepsis (HR, 2.95; P = .001), septic shock (HR, 4.94; P = .038), new organ failures (HR, 2.45; P = .014), and acute-on-chronic liver failure (HR, 2.27; P = .037) than patients without RAI. RAI was associated independently with death within 90 days of diagnosis (subdistribution HR, 4.83; P = .001). Patients with RAI and mild renal dysfunction or hepatic encephalopathy had no significant difference in cumulative incidence of 28-day mortality vs patients with acute-on-chronic liver failure grade 1 (25% vs 22%). CONCLUSIONS We found RAI to occur in almost half of patients admitted to a hospital for acute decompensation of cirrhosis. RAI was associated with a deficit of substrates for steroidogenesis and an increase in markers of inflammation. Patients with RAI have a high risk of developing sepsis, septic shock, organ failure, and death within 90 days. RAI has similar prognostic value to nonrenal organ failures.
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Affiliation(s)
- Salvatore Piano
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Elisa Favaretto
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Marta Tonon
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Giorgia Antonelli
- Unit of Laboratory Medicine, Department of Medicine, University of Padova, Padova, Italy
| | - Alessandra Brocca
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Antonietta Sticca
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Sara Mareso
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Carla Scaroni
- Unit of Endocrinology, Department of Medicine, University of Padova, Padova, Italy
| | - Mario Plebani
- Unit of Laboratory Medicine, Department of Medicine, University of Padova, Padova, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy.
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24
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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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25
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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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26
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Velez JCQ, Therapondos G, Juncos LA. Reappraising the spectrum of AKI and hepatorenal syndrome in patients with cirrhosis. Nat Rev Nephrol 2019; 16:137-155. [PMID: 31723234 DOI: 10.1038/s41581-019-0218-4] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2019] [Indexed: 12/12/2022]
Abstract
The occurrence of acute kidney injury (AKI) in patients with end-stage liver disease constitutes one of the most challenging clinical scenarios in in-hospital and critical care medicine. Hepatorenal syndrome type 1 (HRS-1), which is a specific type of AKI that occurs in the context of advanced cirrhosis and portal hypertension, is associated with particularly high mortality. The pathogenesis of HRS-1 is largely viewed as a functional derangement that ultimately affects renal vasculature tone. However, new insights suggest that non-haemodynamic tubulo-toxic factors, such as endotoxins and bile acids, might mediate parenchymal renal injury in patients with cirrhosis, suggesting that concurrent mechanisms, including those traditionally associated with HRS-1 and non-traditional factors, might contribute to the development of AKI in patients with cirrhosis. Moreover, histological evidence of morphological abnormalities in the kidneys of patients with cirrhosis and renal dysfunction has prompted the functional nature of HRS-1 to be re-examined. From a clinical perspective, a diagnosis of HRS-1 guides utilization of vasoconstrictive therapy and decisions regarding renal replacement therapy. Patients with cirrhosis are at risk of AKI owing to a wide range of factors. However, the tools currently available to ascertain the diagnosis of HRS-1 and guide therapy are suboptimal. Short of liver transplantation, goal-directed haemodynamically targeted pharmacotherapy remains the cornerstone of treatment for this condition; improved understanding of the underlying pathogenic mechanisms might lead to better clinical outcomes. Here, we examine our current understanding of the pathophysiology of HRS-1 and existing challenges in its diagnosis and treatment.
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Affiliation(s)
- Juan Carlos Q Velez
- Department of Nephrology, Ochsner Clinic Foundation, New Orleans, LA, USA. .,Ochsner Clinical School, The University of Queensland, Brisbane, Australia.
| | - George Therapondos
- Department of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, LA, USA
| | - Luis A Juncos
- Division of Nephrology, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.,Renal Section, Department of Medicine, Central Arkansas Veterans Affairs Medical Center, Little Rock, AR, USA
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Chen P, Wang YY, Chen C, Guan J, Zhu HH, Chen Z. The immunological roles in acute-on-chronic liver failure: An update. Hepatobiliary Pancreat Dis Int 2019; 18:403-411. [PMID: 31303562 DOI: 10.1016/j.hbpd.2019.07.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 06/10/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) refers to the acute deterioration of liver function that occurs in patients with chronic liver disease. ACLF is characterized by acute decompensation, organ failure and high short-term mortality. Numerous studies have been conducted and remarkable progress has been made regarding the pathophysiology and pathogenesis of this disease in the last decade. The present review was to summarize the advances in this field. DATA SOURCES A comprehensive search in PubMed and EMBASE was conducted using the medical subject words "acute-on-chronic liver failure", "ACLF", "pathogenesis", "predictors", and "immunotherapy" combined with free text terms such as "systemic inflammation" and "immune paralysis". Relevant papers published before October 31, 2018, were included. RESULTS ACLF has two marked pathophysiological features, namely, excessive systemic inflammation and susceptibility to infection. The systemic inflammation is mainly manifested by a significant increase in the levels of plasma pro-inflammatory factors, leukocyte count and C-reactive protein. The underlying mechanisms are unclear and may be associated with decreased immune inhibitory cells, abnormal expression of cell surface molecules and intracellular regulatory pathways in immune cells and increased damage-associated molecular patterns in circulation. However, the main cause of susceptibility to infection is immune paralysis. Immunological paralysis is characterized by an attenuated activity of immune cells. The mechanisms are related to elevations of immune inhibitory cells and the concentration of plasma anti-inflammatory molecules. Some immune biological indicators, such as soluble CD163, are used to explore the pathogenesis and prognosis of the disease, and some immunotherapies, such as glucocorticoids and granulocyte colony-stimulating factor, are effective on ACLF. CONCLUSIONS Overwhelming systemic inflammation and susceptibility to infection are two key features of ACLF. A better understanding of the state of a patient's immune system will help to guide immunotherapy for ACLF.
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Affiliation(s)
- Ping Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China
| | - Yun-Yun Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China
| | - Chao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China
| | - Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China
| | - Hai-Hong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.
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28
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Simonetto DA, Piccolo Serafim L, Gallo de Moraes A, Gajic O, Kamath PS. Management of Sepsis in Patients With Cirrhosis: Current Evidence and Practical Approach. Hepatology 2019; 70:418-428. [PMID: 30516866 DOI: 10.1002/hep.30412] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 11/30/2018] [Indexed: 12/13/2022]
Abstract
Sepsis in patients with cirrhosis is associated with high mortality. An impaired immune response accounts for the increased infection risk observed in these patients. Hemodynamic and systemic changes suggestive of sepsis may be observed in patients with cirrhosis in the absence of infection; therefore, diagnosis and treatment of sepsis may be delayed. The optimal management of the critically ill patient with sepsis and cirrhosis has not been well established and is generally extrapolated from consensus guidelines and expert recommendations made for management of patients without cirrhosis with sepsis. Despite the lack of strong evidence, we propose a contemporary pragmatic approach to sepsis management in patients with cirrhosis, including the choice of fluids, vasopressors, and antibiotics.
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Affiliation(s)
- Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Laura Piccolo Serafim
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN.,Multidisciplinary Epidemiology and Translational Research in Intensive Care (METRIC), Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Alice Gallo de Moraes
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN.,Multidisciplinary Epidemiology and Translational Research in Intensive Care (METRIC), Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Ognjen Gajic
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN.,Multidisciplinary Epidemiology and Translational Research in Intensive Care (METRIC), Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
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29
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Theocharidou E, Giouleme O, Anastasiadis S, Markopoulou A, Pagourelias E, Vassiliadis T, Fotoglidis A, Agorastou P, Slavakis A, Balaska A, Kouskoura MG, Gossios TD, Karagiannis A, Mantzoros CS. Free Cortisol Is a More Accurate Marker for Adrenal Function and Does Not Correlate with Renal Function in Cirrhosis. Dig Dis Sci 2019; 64:1686-1694. [PMID: 30659471 DOI: 10.1007/s10620-019-5460-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 01/08/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND The accuracy of diagnosis and clinical implications of the hepatoadrenal syndrome, as currently diagnosed using total cortisol, remain to be validated. AIM The aim of this study was to assess adrenal function using free cortisol in stable cirrhosis and study the potential implications of any abnormalities for renal and/or cardiac function. METHODS Sixty-one stable consecutively enrolled patients with cirrhosis underwent assessment of adrenal function using the low-dose short Synacthen test, renal function by 51Cr-EDTA glomerular filtration rate (GFR), and cardiac function by two-dimensional echocardiography. RESULTS Eleven patients (18%) had total peak cortisol (PC) < 500 nmol/L, but no patient had free PC < 33 nmol/L indicating that diagnosis of AI using total cortisol is not confirmed using free cortisol. Free cortisol did not correlate with GFR or parameters of cardiac function. Patients with higher Child-Pugh class had progressively lower free cortisol. Patients with low GFR < 60 mL/min (N = 22) had more frequently grade II-III diastolic dysfunction (66.7% vs. 17.6%; p = 0.005) and had higher Child-Pugh and MELD score compared to those with normal GFR. CONCLUSIONS Diagnosis of AI using total cortisol is not confirmed using free cortisol and is thus considered unreliable in cirrhosis. Free cortisol is not associated with renal or cardiac dysfunction. Lower free cortisol in more advanced stages of liver disease might be secondary to decreased synthesis due to lower cholesterol levels. Irrespective of free cortisol, parameters of cardiac dysfunction are associated with renal impairment supporting the cardio-renal hypothesis.
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Affiliation(s)
| | - Olga Giouleme
- 2nd Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Sotirios Anastasiadis
- 2nd Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Aikaterini Markopoulou
- School of Pharmacy, Laboratory of Pharmaceutical Analysis, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Efstathios Pagourelias
- 3rd Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Themistoklis Vassiliadis
- 3rd Department of Internal Medicine, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Athanasios Fotoglidis
- 3rd Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Polyxeni Agorastou
- 2nd Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Aristeidis Slavakis
- Department of Biochemistry, Hippokration General Hospital, Thessaloníki, Greece
| | - Aikaterini Balaska
- Laboratory of the 2nd Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Maria G Kouskoura
- School of Pharmacy, Laboratory of Pharmaceutical Analysis, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Thomas D Gossios
- 2nd Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Asterios Karagiannis
- 2nd Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Christos S Mantzoros
- Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
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30
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Kennedy L, Nagiah S. A case of severe rhabdomyolysis associated with secondary adrenal insufficiency and autoimmune hepatitis. BMJ Case Rep 2019; 12:12/3/e227343. [PMID: 30898957 PMCID: PMC6453326 DOI: 10.1136/bcr-2018-227343] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Rhabdomyolysis is a serious and life-threatening condition which has many established causes including endocrine disturbances. Of those, thyroid, adrenal and pituitary deficiencies are the most commonly seen. Most cases of rhabdomyolysis with adrenal insufficiency that have been reported have been primary. Here, we report an encounter with a patient who presented with her second case of severe rhabdomyolysis in the setting of secondary adrenal insufficiency. The cause for corticotropic suppression was most likely autoimmune hypophysitis given the presence of other autoimmune comorbidities including a new diagnosis of autoimmune hepatitis. In addition to her case, we present a brief review of the literature pertaining to cases of rhabdomyolysis attributed to adrenal insufficiency.
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Affiliation(s)
- Lisa Kennedy
- General Medicine, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Sureshkumar Nagiah
- General Medicine, Flinders Medical Centre, Bedford Park, South Australia, Australia
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31
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Theiler-Schwetz V, Zaufel A, Schlager H, Obermayer-Pietsch B, Fickert P, Zollner G. Bile acids and glucocorticoid metabolism in health and disease. Biochim Biophys Acta Mol Basis Dis 2019; 1865:243-251. [DOI: 10.1016/j.bbadis.2018.08.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 07/18/2018] [Accepted: 08/01/2018] [Indexed: 12/12/2022]
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32
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Deep A, Saxena R, Jose B. Acute kidney injury in children with chronic liver disease. Pediatr Nephrol 2019; 34:45-59. [PMID: 29497824 PMCID: PMC6244855 DOI: 10.1007/s00467-018-3893-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 01/10/2018] [Accepted: 01/11/2018] [Indexed: 12/16/2022]
Abstract
Acute kidney injury (AKI) is a common accompaniment in patients with liver disease. The causes, risk factors, manifestations and management of AKI in these patients vary according to the liver disease in question (acute liver failure, acute-on-chronic liver failure, post-liver transplantation or metabolic liver disease). There are multiple causes of AKI in patients with liver disease-pre-renal, acute tubular necrosis, post-renal, drug-induced renal failure and hepatorenal syndrome (HRS). Definitions of AKI in liver failure are periodically revised and updated, but pediatric definitions have still to see the light of the day. As our understanding of the pathophysiology of liver disease and renal involvement improves, treatment modalities have become more advanced and rationalized. Treatment includes reversing precipitating factors, such as infections and gastrointestinal bleeding, volume expansion, paracentesis and vasoconstrictors. This approach is tried and tested in adults. A pediatric tailored approach is still lacking due to inadequate numbers of patients, differences in causes of AKI and paucity of literature. In this review, we attempt to explore the pathophysiological basis, treatment modalities and controversies in the diagnosis and treatment of AKI in pediatric patients with chronic liver disease and discuss our own personal practice. We recognize that, although it is not a very commonly encountered entity in pediatric population, HRS has specific diagnostic criteria and treatment modalities that differ from other causes of AKI in patients with chronic liver disease; hence among the etiologies of kidney injury in patients with chronic liver disease, we focus here on HRS.
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Affiliation(s)
- Akash Deep
- Paediatric Intensive Care Unit (PICU), King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
| | - Romit Saxena
- Paediatric Intensive Care Unit (PICU), King’s College Hospital, Denmark Hill, London, SE5 9RS UK
| | - Bipin Jose
- Paediatric Intensive Care Unit (PICU), King’s College Hospital, Denmark Hill, London, SE5 9RS UK
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33
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Akindele AJ, Oludadepo GO, Amagon KI, Singh D, Osiagwu DD. Protective effect of carvedilol alone and coadministered with diltiazem and prednisolone on doxorubicin and 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats. Pharmacol Res Perspect 2018; 6. [PMID: 29417758 PMCID: PMC5817834 DOI: 10.1002/prp2.381] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 11/30/2017] [Indexed: 01/07/2023] Open
Abstract
This study investigated the protective effects of carvedilol alone and coadministered with prednisolone and diltiazem on doxorubicin (DOX) and 5‐fluorouracil (5‐FU)‐induced toxicity. Each of 2 pools of 70 female rats were randomly allotted into 10 groups of 7 animals each and treated as follows: Group 1: normal saline (10 mL/kg); Group 2: normal saline and DOX (40 mg/kg)/5‐FU (20 mg/kg) alone; Group 3: gallic acid (200 mg/kg) and DOX/5‐FU; Group 4: carvedilol (0.075 mg/kg) and DOX/5‐FU; Group 5: carvedilol (0.15 mg/kg) and DOX/5‐FU; Group 6: carvedilol (0.30 mg/kg) and DOX/5‐FU; Group 7: diltiazem (3.43 mg/kg) and DOX/5‐FU; Group 8: diltiazem (3.43 mg/kg), carvedilol (0.15 mg/kg), and DOX/5‐FU; Group 9: prednisolone (0.57 mg/kg) and DOX/5‐FU; and Group 10: prednisolone (0.57 mg/kg), carvedilol (0.15 mg/kg), and DOX/5‐FU. Treatments were done p.o. for 16/14 days for the DOX/5‐FU models. DOX/5‐FU was administered i.p. to the rats in Groups 2‐10 on day 14/10‐14. On day 17/15 (DOX/5‐FU), blood samples were collected, and liver and kidneys of rats were harvested for antioxidant and histopathological assessments. Carvedilol alone and coadministered with prednisolone significantly (P < .05) decreased alanine aminotransferase level compared with administration of DOX alone. Carvedilol alone and coadministered with diltiazem significantly (P < .05) decreased creatinine level compared with administration of DOX/5‐FU alone. Carvedilol alone and coadministered with diltiazem and prednisolone significantly (P < .05) increased the level of hepatic superoxide dismutase and catalase, and decreased malondialdehyde compared with DOX administration alone. Histopathological observations correlated with results of biochemical and antioxidant analyses. Carvedilol administered alone and coadministered with diltiazem and prednisolone reduced the effect of DOX/5‐FU‐induced hepatic and renal toxicities due to enhanced in vivo antioxidant activity. The protective effect was more prominent in the doxorubicin model compared with the 5‐fluorouracil test. Coadministration of carvedilol with either diltiazem or prednisolone did not show better protection relative to carvedilol alone.
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Affiliation(s)
- Abidemi J Akindele
- Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria
| | - Gabriel O Oludadepo
- Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria
| | - Kennedy I Amagon
- Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria.,Department of Pharmacology, Faculty of Pharmaceutical Sciences, University of Jos, Jos, Nigeria
| | - Dhirendra Singh
- Department of Pharmacology, Shakambhari Institute of Higher Education and Technology, Roorkee, India
| | - Daniel D Osiagwu
- Department of Anatomic and Molecular Pathology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria
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Singh RR, Walia R, Sachdeva N, Bhalla A, Singh A, Singh V. Relative adrenal insufficiency in cirrhotic patients with ascites (hepatoadrenal syndrome). Dig Liver Dis 2018; 50:1232-1237. [PMID: 29887344 DOI: 10.1016/j.dld.2018.05.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 04/11/2018] [Accepted: 05/12/2018] [Indexed: 02/08/2023]
Abstract
AIM Relative adrenal insufficiency (RAI) has been reported in critically ill patients with cirrhosis. We evaluated the prevalence of RAI and its relationship to clinical course in non-septic cirrhosis patients with ascites. METHODS The study included 66 consecutive non-septic cirrhosis patients with ascites. RAI was defined by a delta cortisol lower than 9 μg/dL and/or a peak cortisol lower than 18 μg/dL. RESULTS Sixty-six patients with cirrhosis and ascites were studied. The mean Child-Turcotte-Pugh (CTP) and model for end stage liver disease (MELD) scores were 10.6 ± 1.9 and 21.5 ± 7.3, respectively. The prevalence of RAI in patients with cirrhosis and ascites was 47% (31/66). The prevalence of RAI in patients with and without spontaneous bacterial peritonitis, renal failure and type 1 hepatorenal syndrome (HRS) was comparable. Baseline hyponatremia was common in RAI (42% versus 17%, p = 0.026). There was a significant correlation of prevalence of RAI with prothrombin time, international normalized ratio, MELD scores and CTP class. During follow-up, there was no association between RAI and the risk to develop new infections, severe sepsis, type 1 HRS and death. CONCLUSIONS RAI is common in non-septic cirrhotic patients with ascites and its prevalence increases with severity of liver disease. However, it does not affect the short-term outcome in these patients.
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Affiliation(s)
- Rajiv Ranjan Singh
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rama Walia
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Naresh Sachdeva
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashish Bhalla
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Akash Singh
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Virendra Singh
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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Angeli P, Bernardi M, Villanueva C, Francoz C, Mookerjee RP, Trebicka J, Krag A, Laleman W, Gines P. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018; 69:406-460. [PMID: 29653741 DOI: 10.1016/j.jhep.2018.03.024] [Citation(s) in RCA: 1772] [Impact Index Per Article: 253.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 03/28/2018] [Indexed: 02/06/2023]
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An Analysis of the Hypothalamic-Pituitary-Adrenal Axis Functions in Cirrhotic Rats in Response to Surgical Stress. Surg Res Pract 2018; 2018:7606304. [PMID: 30050969 PMCID: PMC6046119 DOI: 10.1155/2018/7606304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Revised: 05/05/2018] [Accepted: 05/20/2018] [Indexed: 11/18/2022] Open
Abstract
Introduction The activation of hypothalamic-pituitary-adrenal (HPA) axis through severe diseases and stress courses leads to a rise in circulatory cortisol for an adequate response to stress. This axis is one of the important systems that involve in neuroendocrine response to the surgical stress. Hepatoadrenal syndrome that is a manifestation of adrenal insufficiency (AI) in the course of liver disease is described as insufficient production of steroid hormones mainly cortisol due to primary dysfunction of the adrenal gland or secondary malfunction of the HPA axis to provoke the adrenal gland leading to severe illness and increased mortality. Through this evidence, we presented this question as to whether cirrhotic patients have a greater mortality rate than other patients after surgery and if the HPA axis is partly responsible for this phenomenon. Also how the adrenal gland functions during surgery in cirrhotic rats. We conducted this study to assess the effect of cirrhosis on the HPA axis through surgery in cirrhotic rats by evaluating the changes in serum corticosterone level and blood sugar before, immediately, and 30 minutes after surgery. Method This study was performed in the animal lab approved by the Ethics Committee of Tehran University of Medical Sciences in 2014, on 25 male Wistar rats. Thioacetamide was used for induction of cirrhosis in rats with new method of monitoring weekly changes of rats' weight which had 100% success in procedure and reduction in mortality rate. Laparotomy was performed on all of the rats during 9–12 in the morning within 10–15 minutes. Laparotomy was chosen as surgical stress because of its simplicity and feasibility. Three blood samples were obtained from each rat immediately after inducing anesthesia, immediately after the conclusion of surgery, and 30 minutes after surgery. The plasma concentration of corticosterone was measured with enzyme-linked immunosorbent assay test. P value of 0.05 or less was considered as statistical significance. Result Cirrhotic rat group consisted of 15 rats and control group consisted of 10 rats. There was a significant difference in the mean level of corticosterone and blood sugar between the cirrhotic rat group and control group in the 3 time levels (P=0.044/P < 0.001). Pairwise comparison of mean corticosterone and blood sugar levels between case (mean: 249.359 ± 3.90) and control (mean: 262.40 ± 4.69) showed a significant difference (P=0.04, 95% CI = 0.30–25.79/P < 0.001, 95% CI = 129.62–233.96). Unlike the control group, the level of serum corticosterone was compared in the cirrhotic rat group (group 1) before, immediately, and 30 minutes after surgery, which showed a significant difference in our study (P value = 0.005). However, this result was also significant in comparing the blood sugar in 3 time levels of surgery in the control group (P value < 0.001) but not in the cirrhotic rat group (P value = 0.233). Conclusion There was a significant rise in corticosterone levels during 3 time levels of surgery in cirrhotic rats; nevertheless, this elevation was significantly lower than the control group. Also the mean level of blood sugar was higher in the control group than in cirrhotic rats. However, this difference was significant in comparison with the same times of surgery between the two groups. These results approximately can substantiate our hypothesis that AI in the field of cirrhosis would also affect the response of HPA axis to stress during and after surgery that can be concomitant with higher rate of cardiovascular unsteadiness incidences, deteriorating the severity of illness and rise in mortality rate.
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Zou X, Ramachandran P, Kendall TJ, Pellicoro A, Dora E, Aucott RL, Manwani K, Man TY, Chapman KE, Henderson NC, Forbes SJ, Webster SP, Iredale JP, Walker BR, Michailidou Z. 11Beta-hydroxysteroid dehydrogenase-1 deficiency or inhibition enhances hepatic myofibroblast activation in murine liver fibrosis. Hepatology 2018; 67:2167-2181. [PMID: 29251794 PMCID: PMC6001805 DOI: 10.1002/hep.29734] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 11/16/2017] [Accepted: 12/07/2017] [Indexed: 12/13/2022]
Abstract
A hallmark of chronic liver injury is fibrosis, with accumulation of extracellular matrix orchestrated by activated hepatic stellate cells (HSCs). Glucocorticoids limit HSC activation in vitro, and tissue glucocorticoid levels are amplified by 11beta-hydroxysteroid dehydrogenase-1 (11βHSD1). Although 11βHSD1 inhibitors have been developed for type 2 diabetes mellitus and improve diet-induced fatty liver in various mouse models, effects on the progression and/or resolution of liver injury and consequent fibrosis have not been characterized. We have used the reversible carbon tetrachloride-induced model of hepatocyte injury and liver fibrosis to show that in two models of genetic 11βHSD1 deficiency (global, Hsd11b1-/- , and hepatic myofibroblast-specific, Hsd11b1fl/fl /Pdgfrb-cre) 11βHSD1 pharmacological inhibition in vivo exacerbates hepatic myofibroblast activation and liver fibrosis. In contrast, liver injury and fibrosis in hepatocyte-specific Hsd11b1fl/fl /albumin-cre mice did not differ from that of controls, ruling out 11βHSD1 deficiency in hepatocytes as the cause of the increased fibrosis. In primary HSC culture, glucocorticoids inhibited expression of the key profibrotic genes Acta2 and Col1α1, an effect attenuated by the 11βHSD1 inhibitor [4-(2-chlorophenyl-4-fluoro-1-piperidinyl][5-(1H-pyrazol-4-yl)-3-thienyl]-methanone. HSCs from Hsd11b1-/- and Hsd11b1fl/fl /Pdgfrb-cre mice expressed higher levels of Acta2 and Col1α1 and were correspondingly more potently activated. In vivo [4-(2-chlorophenyl-4-fluoro-1-piperidinyl][5-(1H-pyrazol-4-yl)-3-thienyl]-methanone administration prior to chemical injury recapitulated findings in Hsd11b1-/- mice, including greater fibrosis. CONCLUSION 11βHSD1 deficiency enhances myofibroblast activation and promotes initial fibrosis following chemical liver injury; hence, the effects of 11βHSD1 inhibitors on liver injury and repair are likely to be context-dependent and deserve careful scrutiny as these compounds are developed for chronic diseases including metabolic syndrome and dementia. (Hepatology 2018;67:2167-2181).
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Affiliation(s)
- Xiantong Zou
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
| | | | - Timothy J. Kendall
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
| | | | - Elena Dora
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
| | - Rebecca L. Aucott
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
| | - Kajal Manwani
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
| | - Tak Yung Man
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
| | - Karen E. Chapman
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
| | - Neil C. Henderson
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
| | - Stuart J. Forbes
- MRC Centre for Regenerative MedicineQueen's Medical Research InstituteEdinburghUK
| | - Scott P. Webster
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
| | - John P. Iredale
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
| | - Brian R. Walker
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
| | - Zoi Michailidou
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
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Cholongitas E, Goulis I, Pagkalidou E, Haidich A, Karagiannis A, Nakouti T, Pipili C, Oikonomou T, Gerou S, Akriviadis E. Relative Adrenal Insufficiency is Associated with the Clinical Outcome in Patients with Stable Decompensated Cirrhosis. Ann Hepatol 2018; 16:584-590. [PMID: 28611262 DOI: 10.5604/01.3001.0010.0298] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The clinical impact of relative adrenal insufficiency (AI) on patients with stable decompensated cirrhosis (DeCi) has not been yet elucidated. AIM Explore the association between AI and outcome [death or liver transplantation (LT)] in patients with DeCi. MATERIAL AND METHODS Patients with DeCi presenting no active complication have been included. Clinical and laboratory data, including serum levels of corticosteroid-binding globulin (CBG), interleukin (IL)-1b, IL-6 and tumor necrosis factor (TNFα) were recorded in each participant. Salivary cortisol (SC) and serum total cortisol (STC) were assessed at (T0) and 1 h (T60) after intravenous injection of 250 μg corticotropin. RESULTS 113 consecutive patients were totally tested. Median SC was 3.9 ng/mL and 15.5 ng/mL and median STC was 10.7 μg/dL and 22.7 μg/dL at T0 and T60 respectively. The patients with AI [group 1, n = 34 (30%)] had significantly lower systolic blood pressure (106 ± 12 vs. 113 ± 13 mmHg, p = 0.05), serum sodium (133 ± 7 vs. 137 ± 12 mEq/ L, p = 0.04), HDL (29.9 ± 14 vs. 38.6 ± 18 mg/dL, p = 0.034) and albumin (2.7 ± 0.5 vs. 3.1 ± 0.5 g/dL, p = 0.002), but higher direct bilirubin (median: 1.6 vs. 0.8 mg/dL, p = 0.029) compared to those without AI [group 2, n = 79 (70%)]. Moreover, group 1 patients presented more frequently past history of spontaneous bacterial peritonitis (SBP) [10/34 (29.4%) vs. 6/79 (7.5%), p = 0.002]. AI was significantly associated with death [HR = 2.65, 95% C.I.: 1.55 - 4.52, p = 0.003 over a follow up period of 12 (6-48) months.] Conclusions. The presence of AI in patients with stable DeCi predispose to obvious clinical implications since it is associated with circulatory dysfunction, previous history of SBP and worse survival.
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Affiliation(s)
- Evangelos Cholongitas
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
| | - Ioannis Goulis
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
| | - Eirini Pagkalidou
- Department of Hygiene and Epidemiology, School of Medicine, Thessaloniki, Greece
| | - Anna Haidich
- Department of Hygiene and Epidemiology, School of Medicine, Thessaloniki, Greece
| | - Apostolos Karagiannis
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
| | - Theodora Nakouti
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
| | - Chrysoula Pipili
- Division of Nephrology, Queen Elizabeth University Hospital, Glasgow, UK
| | - Theodora Oikonomou
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
| | - Spyros Gerou
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
| | - Evangelos Akriviadis
- 4th Department of Internal Medicine, Hippokration General Hospital, Medical School Aristotle University of Thessaloniki, Greece
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Ferrarese A, Zanetto A, Becchetti C, Sciarrone SS, Shalaby S, Germani G, Gambato M, Russo FP, Burra P, Senzolo M. Management of bacterial infection in the liver transplant candidate. World J Hepatol 2018; 10:222-230. [PMID: 29527258 PMCID: PMC5838441 DOI: 10.4254/wjh.v10.i2.222] [Citation(s) in RCA: 13] [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: 12/14/2017] [Revised: 12/29/2017] [Accepted: 01/23/2018] [Indexed: 02/06/2023] Open
Abstract
Bacterial infection (BI) is a common cause of impairment of liver function in patients with cirrhosis, especially in the liver transplant candidates. These patients share an immunocompromised state and increased susceptibility to develop community and hospital-acquired infections. The changing epidemiology of BI, with an increase of multidrug resistant strains, especially in healthcare-associated settings, represents a critical issue both in the waiting list and in the post-operative management. This review focused on the role played by BI in patients awaiting liver transplantation, evaluating the risk of drop-out from the waiting list, the possibility to undergo liver transplantation after recovery from infection or during a controlled infection.
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Affiliation(s)
- Alberto Ferrarese
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Chiara Becchetti
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Salvatore Stefano Sciarrone
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Sarah Shalaby
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Giacomo Germani
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Martina Gambato
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Marco Senzolo
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
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Abstract
Critical illness is accompanied by hypothalamic-pituitary-adrenal axis activation, but adrenal insufficiency characterized by inadequate glucocorticoid synthesis is common in critically ill cirrhotic patients, the "hepato-adrenal syndrome." Adrenal cortex also synthesizes androgen (dehydroepiandrosterone, DHEA). DHEA maintains microcirculation by enhancing vascular endothelial nitric oxide synthase (eNOS) activity. In critical patients of other disease entities, a shift of adrenal steroidogenesis away from androgens toward glucocorticoid has been noted, arousing interests in androgen replacement in critical settings. Nevertheless, this has not been surveyed in cirrhosis with hemorrhage. In this study, liver cirrhosis was induced with common bile duct ligation (BDL) in Spraque-Dawley rats. Sham rats were controls. DHEA or vehicle was injected at the beginning of hemorrhage-transfused procedure, followed by terlipressin injection. Hemodynamic parameters were measured. Then abdominal aorta, superior mesenteric arteries (SMA) and splenorenal shunt (prominent portosystemic collateral vessel in rodents) eNOS and inducible NOS protein expressions were evaluated. In bleeding BDL groups without terlipressin injection, adrenocorticotropic hormone (ACTH) stimulation test was performed to evaluate the DHEA response. The results showed that DHEA significantly elevated mean arterial pressure, cardiac output, and stroke volume of bleeding cirrhotic rats treated with terlipressin and reduced systemic vascular resistance without affecting SMA flow, resistance, and portal pressure. DHEA upregulated abdominal aorta and SMA eNOS expressions. ACTH did not stimulate DHEA synthesis in bleeding BDL rats. In conclusion, androgen deficiency exists in bleeding cirrhotic rats. DHEA augments terlipressin-induced amelioration of shock without influencing splanchnic hemodynamics, possibly rendering it a feasible adjunct to vasoconstrictors in variceal hemorrhage.
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Tsai MH, Huang HC, Peng YS, Chen YC, Tian YC, Yang CW, Lien JM, Fang JT, Wu CS, Hsieh SY, Lee FY. Dehydroepiandrosterone sulfate and dehydroepiandrosterone sulfate/cortisol ratio in cirrhotic patients with septic shock: another sign of hepatoadrenal syndrome? Crit Care 2017; 21:214. [PMID: 28810889 PMCID: PMC5557480 DOI: 10.1186/s13054-017-1768-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 06/20/2017] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Cirrhotic patients are susceptible to sepsis and critical illness-related corticosteroid insufficiency (CIRCI). Dehydroepiandrosterone sulfate (DHEAS) is a corticotropin-dependent adrenal androgen, which has immunostimulating and antiglucocorticoid effects. Considering the synchronized synthesis of cortisol and DHEAS and their opposing effects to each other, investigators have proposed measuring these two hormones as a ratio. Severe sepsis has been associated with low DHEAS, especially relative to high cortisol. Despite growing interest in the role of adrenal androgen replacement in critical illness, there have been no data about DHEAS and the DHEAS/cortisol ratio in patients with liver cirrhosis. We studied whether low concentrations of DHEAS and decreased DHEAS/cortisol ratio are associated with poor outcome in patients with liver cirrhosis and septic shock. METHODS We recruited 46 cirrhotic patients with septic shock, and 46 noncirrhotic counterparts matched by age and sex. We evaluated adrenal function using the short corticotropin stimulation test and analyzed the relation between DHEAS and cortisol. RESULTS While the nonsurvivors in the cirrhotic group had significantly lower baseline DHEAS, lower baseline DHEAS/cortisol ratio, and reduced increments of both DHEAS and cortisol upon corticotropin stimulation, the survivors had lower baseline cortisol. Cirrhotic patients with lower DHEAS/cortisol ratio (<1.50) had higher levels of interleukin-6 and tumor necrosis factor alpha, higher Sequential Organ Failure Assessment scores, and higher rates of CIRCI and hospital mortality. Using the area under the receiver operating characteristic (AUROC) curve, both DHEAS and the DHEAS/cortisol ratio demonstrated a good discriminative power for predicting hospital survival (AUROC 0.807 and 0.925 respectively). The cirrhotic group had lower DHEAS and DHEAS/cortisol ratio but higher rates of CIRCI and hospital mortality, compared to the noncirrhotic group. CONCLUSIONS There is dissociation between cortisol (increased) and DHEAS (decreased) in those cirrhotic patients who succumb to septic shock. Low DHEAS/cortisol ratios are associated with more severe diseases, inflammation, and CIRCI and can serve as a prognostic marker. More investigations are needed to evaluate the role of adrenal androgen in this clinical setting.
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Affiliation(s)
- Ming-Hung Tsai
- Division of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Hui-Chun Huang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Veteran General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei, 11217 Taiwan
- Faculty of Medicine, Yang-Ming University School of Medicine, Taipei, Taiwan
- Division of General Medicine, Department of Medicine, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Yun-Shing Peng
- Division of Endocrinology, Chang Gung Memorial Hospital, Chia-Yi, Taiwan
- Chang Gung University, Taoyuan, Taiwan
| | - Yung-Chang Chen
- Chang Gung University, Taoyuan, Taiwan
- Division of Critical Care Nephrology, Kidney Institute, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Ya-Chung Tian
- Chang Gung University, Taoyuan, Taiwan
- Division of Critical Care Nephrology, Kidney Institute, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Chih-Wei Yang
- Chang Gung University, Taoyuan, Taiwan
- Division of Critical Care Nephrology, Kidney Institute, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Jau-Min Lien
- Division of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Ji-Tseng Fang
- Chang Gung University, Taoyuan, Taiwan
- Division of Critical Care Nephrology, Kidney Institute, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Cheng-Shyong Wu
- Chang Gung University, Taoyuan, Taiwan
- Division of Gastroenterology, Chang Gung Memorial Hospital, Chia-Yi, Taiwan
| | - Sen-Yung Hsieh
- Division of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Fa-Yauh Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Veteran General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei, 11217 Taiwan
- Faculty of Medicine, Yang-Ming University School of Medicine, Taipei, Taiwan
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The multiple adrenocorticotropic hormone injections significantly alters hepatic proteome in growing pigs. Livest Sci 2017. [DOI: 10.1016/j.livsci.2017.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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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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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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Fialla AD, Thiesson HC, Bie P, Schaffalitzky de Muckadell OB, Krag A. Internal dysregulation of the renin system in patients with stable liver cirrhosis. Scandinavian Journal of Clinical and Laboratory Investigation 2017; 77:298-309. [DOI: 10.1080/00365513.2017.1308546] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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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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Dionigi E, Garcovich M, Borzio M, Leandro G, Majumdar A, Tsami A, Arvaniti V, Roccarina D, Pinzani M, Burroughs AK, O'Beirne J, Tsochatzis EA. Bacterial Infections Change Natural History of Cirrhosis Irrespective of Liver Disease Severity. Am J Gastroenterol 2017; 112:588-596. [PMID: 28220780 DOI: 10.1038/ajg.2017.19] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 01/18/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVES We assessed the prognostic significance of infections in relation to current prognostic scores and explored if infection could be considered per se a distinct clinical stage in the natural history of cirrhosis. METHODS We included consecutive patients with cirrhosis admitted to a tertiary referral liver unit for at least 48 h over a 2-year period. Diagnosis of infection was based on positive cultures or strict established criteria. We used competing risk analysis and propensity score matching for data analysis. RESULTS 501 patients (63% male, 48% alcoholic liver disease, median Model of End-stage Liver Disease (MELD)=17) underwent 781 admissions over the study period. Portal hypertensive bleeding and complicated ascites were the commonest reasons of admission. The incidence of proven bacterial infection was 25.6% (60% community acquired and 40% nosocomial). Survival rates at 3, 6, 12, and 30 months were 83%, 77%, 71%, and 62% in patients without diagnosis of infection, vs. 50%, 46%, 41%, and 34% in patients with diagnosis of infection. Overall survival was independently associated with MELD score (hazards ratio (HR) 1.099), intensive care (ITU) stay (HR 1.967) and bacterial infection (HR 2.226). Bacterial infection was an independent predictor of survival even when patients who died within the first 30 days were excluded from the analysis in Cox regression (HR 2.013) and competing risk Cox models in all patients (HR 1.46) and propensity risk score-matched infected and non-infected patients (HR 1.67). CONCLUSIONS Infection most likely represents a distinct prognostic stage of cirrhosis, which affects survival irrespective of disease severity, even after recovery from the infective episode.
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Affiliation(s)
- Elena Dionigi
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
- Unità di Gastroenterologia, Azienda Ospedaliera di Melegnano, Vizzolo Predabissi, Italy
| | - Matteo Garcovich
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - Mauro Borzio
- Unità di Gastroenterologia, Azienda Ospedaliera di Melegnano, Vizzolo Predabissi, Italy
| | - Gioacchino Leandro
- National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Castellana Grotte, Italy
| | - Avik Majumdar
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - Aikaterini Tsami
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - Vasiliki Arvaniti
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - Davide Roccarina
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - Andrew K Burroughs
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - James O'Beirne
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
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Abstract
Feline hepatic lipidosis (FHL) is a common and potentially fatal liver disorder. Although the pathophysiologic mechanisms of FHL remain elusive, there is an imbalance between the influx of fatty acids from peripheral fat stores into the liver, de novo liposynthesis, and the rate of hepatic oxidation and dispersal of hepatic TAG via excretion of very-low density lipoproteins. The diagnosis of FHL is based on anamnestic, clinical, and clinicopathologic findings, associated with diagnostic imaging of the liver, and cytology, or histological examination of liver biopsies. Fluid therapy, electrolyte correction and adequate early nutrition are essential components of the therapy for FHL.
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Affiliation(s)
- Chiara Valtolina
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, 3584 CM, Utrecht, The Netherlands.
| | - Robert P Favier
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, 3584 CM, Utrecht, The Netherlands
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Abstract
Cats with cholestatic liver disease experience significant morbidity and mortality when they undergo invasive procedures under anesthesia. Although inadequate adrenal response might account for these outcomes, adrenal function in cats with cholestatic liver disease has not been documented, to our knowledge. The goal of our study was to describe adrenal function in these cats. Twenty-seven cats with a serum bilirubin >230 µmol/L (3 mg/dL) and serum alanine aminotransferase >2 times the upper limit of normal had pre- and 60-min post-adrenocorticotropic hormone (ACTH) cortisol analysis after administration of 5 µg/kg cosyntropin intravenously. The change in cortisol concentrations (delta cortisol) was calculated. Pre- and post-ACTH cortisol concentrations were compared to reference values. Pre-ACTH, post-ACTH, and delta cortisol values were compared between cats surviving to discharge or for 30 d postdischarge. Mean pre-ACTH cortisol levels (205 ± 113 nmol/L [7.4 ± 4.2 µg/dL]) and post-ACTH cortisol levels (440 ± 113 nmol/L [15.9 ± 4.1 g/dL]) in cholestatic cats were significantly greater than reference values in clinically normal cats. There was no association of pre- or post-ACTH cortisol with survival. Cats with a delta cortisol <179 nmol/L (6.5 µg/dL) were more likely to be non-survivors at 30 d post-discharge ( p = 0.037) than cats with delta cortisol >179 nmol/L (6.5 µg/dL). Results indicate that cats with cholestasis have high basal and ACTH-stimulated cortisol values. A delta cortisol <179 nmol/L (6.5 µg/dL) defines a population of cats that have decreased 30-d survival.
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Affiliation(s)
- Faith I Buckley
- Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, Grafton, MA
| | - Orla Mahony
- Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, Grafton, MA
| | - Cynthia R L Webster
- Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, Grafton, MA
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Bertino G, Privitera G, Purrello F, Demma S, Crisafulli E, Spadaro L, Koukias N, Tsochatzis EA. Emerging hepatic syndromes: pathophysiology, diagnosis and treatment. Intern Emerg Med 2016; 11:905-16. [PMID: 27273018 DOI: 10.1007/s11739-016-1478-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 05/25/2016] [Indexed: 12/11/2022]
Abstract
Liver cirrhosis is a major cause of morbidity and mortality worldwide, mainly due to complications of portal hypertension. In this article, we review the current understanding on the pathophysiology, the diagnostic criteria and the available therapeutic options for patients with emerging hepatic syndromes in cirrhosis, namely the hepatorenal, hepato-adrenal and hepatopulmonary syndrome. The hepatorenal syndrome is a well-recognized complication of advanced cirrhosis and is usually associated with an accelerated course to death unless liver transplantation is performed. The hepatopulmonary syndrome is often missed in the evaluation of patients with cirrhosis; however, early recognition is essential for the efficient management of individual patients. The hepato-adrenal syndrome, although not fully characterized, offers an exciting field for research and potential therapeutic interventions.
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Affiliation(s)
- Gaetano Bertino
- Hepatology Unit, Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Catania, Italy
| | - Graziella Privitera
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi-Nesima, Catania, Italy
| | - Francesco Purrello
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi-Nesima, Catania, Italy
| | - Shirin Demma
- Hepatology Unit, Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Catania, Italy
| | - Emanuele Crisafulli
- Hepatology Unit, Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Catania, Italy
| | - Luisa Spadaro
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi-Nesima, Catania, Italy
| | - Nikolaos Koukias
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK.
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