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Lapenna L, Di Cola S, Merli M. The crucial role of risk factors when dealing with hepatic Encephalopathy. Metab Brain Dis 2024; 40:29. [PMID: 39570425 DOI: 10.1007/s11011-024-01446-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 10/11/2024] [Indexed: 11/22/2024]
Abstract
Hepatic encephalopathy (HE) is a common condition in patients with cirrhosis, representing the second most frequent cause of decompensation. Approximately 30-40% of patients with cirrhosis will experience overt HE during the clinical course of their illness. In most cases, it is possible to identify a precipitating or risk factor for HE. These are distinct concepts that play different roles in the development of this condition. While precipitating factors act acutely, risk factors are generally present over an extended period and contribute to the overall likelihood of developing HE. The two types of factors require different approaches, with risk factors being more susceptible to prevention. The aim of this review is to describe the most important risk factors (such as severity of liver disease, previous episode of HE, minimal/covert HE, spontaneous and iatrogenic shunt, malnutrition, chronic therapies, metabolic diseases) for the development of HE and how to prevent it.
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Affiliation(s)
- Lucia Lapenna
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Simone Di Cola
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Manuela Merli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
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Maddock RJ, Vlasova RM, Chen S, Iosif AM, Bennett J, Tanase C, Ryan AM, Murai T, Hogrefe CE, Schumann CD, Geschwind DH, Van de Water J, Amaral DG, Lesh TA, Styner MA, Kimberley McAllister A, Carter CS, Bauman MD. Altered brain metabolites in male nonhuman primate offspring exposed to maternal immune activation. Brain Behav Immun 2024; 121:280-290. [PMID: 39032543 PMCID: PMC11809764 DOI: 10.1016/j.bbi.2024.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/04/2024] [Accepted: 07/15/2024] [Indexed: 07/23/2024] Open
Abstract
Converging data show that exposure to maternal immune activation (MIA) in utero alters brain development in animals and increases the risk of neurodevelopmental disorders in humans. A recently developed non-human primate MIA model affords opportunities for studies with uniquely strong translational relevance to human neurodevelopment. The current longitudinal study used 1H-MRS to investigate the developmental trajectory of prefrontal cortex metabolites in male rhesus monkey offspring of dams (n = 14) exposed to a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid (Poly IC), in the late first trimester. Brain metabolites in these animals were compared to offspring of dams that received saline (n = 10) or no injection (n = 4). N-acetylaspartate (NAA), glutamate, creatine, choline, myo-inositol, taurine, and glutathione were estimated from PRESS and MEGA-PRESS acquisitions obtained at 6, 12, 24, 36, and 45 months of age. Prior investigations of this cohort reported reduced frontal cortical gray and white matter and subtle cognitive impairments in MIA offspring. We hypothesized that the MIA-induced neurodevelopmental changes would extend to abnormal brain metabolite levels, which would be associated with the observed cognitive impairments. Prefrontal NAA was significantly higher in the MIA offspring across all ages (p < 0.001) and was associated with better performance on the two cognitive measures most sensitive to impairment in the MIA animals (both p < 0.05). Myo-inositol was significantly lower across all ages in MIA offspring but was not associated with cognitive performance. Taurine was elevated in MIA offspring at 36 and 45 months. Glutathione did not differ between groups. MIA exposure in male non-human primates is associated with altered prefrontal cortex metabolites during childhood and adolescence. A positive association between elevated NAA and cognitive performance suggests the hypothesis that elevated NAA throughout these developmental stages reflects a protective or resilience-related process in MIA-exposed offspring. The potential relevance of these findings to human neurodevelopmental disorders is discussed.
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Affiliation(s)
- Richard J Maddock
- Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA.
| | - Roza M Vlasova
- Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA
| | - Shuai Chen
- Division of Biostatistics, Department of Public Health Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Ana-Maria Iosif
- Division of Biostatistics, Department of Public Health Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Jeffrey Bennett
- Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Costin Tanase
- Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Amy M Ryan
- Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Takeshi Murai
- Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Casey E Hogrefe
- California National Primate Research Center, University of California Davis, Davis, CA, USA
| | - Cynthia D Schumann
- Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Daniel H Geschwind
- Neurogenetics Program, Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA
| | - Judy Van de Water
- Rheumatology/Allergy and Clinical Immunology, School of Medicine, University of California Davis, Sacramento, CA, USA; MIND Institute, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - David G Amaral
- MIND Institute, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Tyler A Lesh
- Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Martin A Styner
- Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA; Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA
| | | | - Cameron S Carter
- Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA.
| | - Melissa D Bauman
- California National Primate Research Center, University of California Davis, Davis, CA, USA; MIND Institute, School of Medicine, University of California Davis, Sacramento, CA, USA; Physiology and Membrane Biology, School of Medicine, University of California Davis, Sacramento, CA, USA.
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Chauhan M, Zhang T, Thuluvath PJ. Combined effects of hyponatremia and hepatic encephalopathy on inpatient mortality. Ann Hepatol 2023; 28:101084. [PMID: 36878465 DOI: 10.1016/j.aohep.2023.101084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/15/2023] [Accepted: 02/05/2023] [Indexed: 03/08/2023]
Abstract
INTRODUCTION AND OBJECTIVES Although hyponatremia and hepatic encephalopathy (HE) are known independent predictors of mortality, their combined effect is unknown. We investigated whether the inpatient mortality differed among patients with both hyponatremia and HE compared to those with either hyponatremia or HE alone. MATERIALS AND METHODS In this retrospective study, data were extracted from the National Inpatient Sample (NIS) to identify US adults (aged ≥18 years) with cirrhosis between January 1st, 2016, and December 31st, 2017. We analyzed the effects of hyponatremia, HE, or a combination of hyponatremia and HE on inpatient mortality using logistic regression. RESULTS Among 309,841 cirrhosis-related admissions, 22,870 (7%) patients died during hospitalization. Those with a combination of hyponatremia and HE had higher mortality (14%) than those with HE only (11%), hyponatremia only (9%), and neither hyponatremia nor HE (6%) (p<0.001). When compared to patients without hyponatremia or HE, patients with both hyponatremia and HE had the highest odds (adjusted odds ratio or aOR) of inpatient mortality (aOR 1.90, 95% CI: 1.79 - 2.01) followed by patients with HE only (aOR 1.75, 95% CI: 1.69 - 1.82) and patients with hyponatremia only (aOR 1.17, 95% CI: 1.12 - 1.22). Patients with HE only had 50% higher odds of inpatient mortality when compared to those with hyponatremia only (aOR: 1.50, 95% CI: 1.43 - 1.57). CONCLUSIONS In this nationwide study, the presence of both hyponatremia and HE was associated with higher inpatient mortality than either hyponatremia or HE alone.
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Affiliation(s)
- Mahak Chauhan
- Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore, MD, United States
| | - Talan Zhang
- Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore, MD, United States
| | - Paul J Thuluvath
- Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore, MD, United States; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD. United States.
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Old and New Precipitants in Hepatic Encephalopathy: A New Look at a Field in Continuous Evolution. J Clin Med 2023; 12:jcm12031187. [PMID: 36769836 PMCID: PMC9917479 DOI: 10.3390/jcm12031187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Hepatic encephalopathy (HE) is a common complication in patients with advanced liver disease. It is a brain dysfunction characterized by neurological and psychiatric symptoms that significantly affects quality of life, morbidity and mortality of patients. HE has various precipitants that can potentially promote its onset, alone or in combination. Among the historically well-known precipitants, such as infections, gastrointestinal bleeding, dehydration, electrolyte disorders and constipation, recent studies have highlighted the role of malnutrition and portosystemic shunts as new precipitating factors of HE. The identification, management and correction of these factors are fundamental for effective HE treatment, in addition to pharmacological therapy with non-absorbable disaccharides and/or antibiotics.
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Praharaj DL, Anand AC. Clinical Implications, Evaluation, and Management of Hyponatremia in Cirrhosis. J Clin Exp Hepatol 2022; 12:575-594. [PMID: 35535075 PMCID: PMC9077240 DOI: 10.1016/j.jceh.2021.09.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/06/2021] [Indexed: 02/06/2023] Open
Abstract
Hyponatremia is the most common electrolyte abnormality in patients with decompensated cirrhosis on Liver Transplantation (LT) waiting list. Most of these patients have dilutional or hypervolemic hyponatremia secondary to splanchnic vasodilatation. Excessive secretion of the antidiuretic hormone also plays an important role. Hypervolemic hyponatremia is commonly associated with refractory ascites, spontaneous bacterial peritonitis, and hepatic encephalopathy. Although uncommon, the use of diuretics and laxatives can cause hypovolemic hyponatremia that is characterized by the striking absence of ascites or pedal edema. Clinical features are often nonspecific and depend on the acuity of onset rather than the absolute value of serum sodium. Symptoms may be subtle, including nausea, lethargy, weakness, or anorexia. However, rarely patients may present with confusion, seizures, psychosis, or coma. Treatment includes discontinuation of diuretics, beta-blockers, and albumin infusion. Hypertonic saline (3%) infusion may be used in patients with very low serum sodium (<110 mmol/L) or when patients present with seizures or coma. Short-term use of Vasopressin (V2) receptor antagonists may also be used to normalize sodium levels prior to LT. However, all these measures may be futile, and LT remains the definite treatment in these patients to improve survival. In this review, we describe the classification, pathogenesis of hyponatremia, and its clinical implications in patients with cirrhosis. Approach to these patients along with management will also be discussed briefly.
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Key Words
- ACE, angiotensin-converting enzyme
- ACLF, acute-on-chronic liver failure
- ACTH, adrenocorticotropic hormone
- ADH
- ADH, antidiuretic hormone
- AKI, acute kidney injury
- AVP, arginine vasopressin
- CLIF, chronic liver failure
- CNS, central nervous system
- CTP, Child-Turcotte-Pugh
- CVVHD, continuous venovenous hemofiltration
- DAMP, damage-associated molecular patterns
- EABV, effective arterial blood volume
- FENa, fractional excretion of sodium
- HE, hepatic encephalopathy
- HRS, hepatorenal syndrome
- LT, liver transplantation
- LVP, large volume paracentesis
- MAP, mean arterial pressure
- MELD, model of end-stage liver disease
- NO, nitric oxide
- NSBB, nonselective beta-blockers
- PAMP, pathogen-associated molecular patterns
- PICD, paracentesis-induced circulatory dysfunction
- PPCD, post-paracentesis circulatory dysfunction
- PRA, plasma renin activity
- RA, refractory ascites
- RAAS, renin-angiotensin-aldosterone-system
- RAI, relative adrenal insufficiency
- RBF, renal blood flow
- SBP, spontaneous bacterial peritonitis
- SIADH, syndrome of inappropriate ADH secretion
- SMT, standard medical treatment
- SNS, sympathetic nervous system
- TBW, total body water
- TIPS, transjugular intrahepatic portosystemic shunt
- advanced cirrhosis
- albumin
- hyponatremia
- liver transplantation
- sNa, serum sodium
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Affiliation(s)
- Dibya L. Praharaj
- Address for correspondence. Dibya L Praharaj, Assistant Professor, Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Science, Bhubaneswar, India
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El-Abtah ME, Wenke MR, Talati P, Fu M, Kim D, Weerasekera A, He J, Vaynrub A, Vangel M, Rapalino O, Andronesi O, Arrillaga-Romany I, Forst DA, Yen YF, Rosen B, Batchelor TT, Gonzalez RG, Dietrich J, Gerstner ER, Ratai EM. Myo-Inositol Levels Measured with MR Spectroscopy Can Help Predict Failure of Antiangiogenic Treatment in Recurrent Glioblastoma. Radiology 2021; 302:410-418. [PMID: 34751617 PMCID: PMC8805659 DOI: 10.1148/radiol.2021210826] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Background Patients with recurrent glioblastoma (GBM) are often treated with antiangiogenic agents, such as bevacizumab (BEV). Despite therapeutic promise, conventional MRI methods fail to help determine which patients may not benefit from this treatment. Purpose To use MR spectroscopic imaging (MRSI) with intermediate and short echo time to measure corrected myo-inositol (mI)normalized by contralateral creatine (hereafter, mI/c-Cr) in participants with recurrent GBM treated with BEV and to investigate whether such measurements can help predict survivorship before BEV initiation (baseline) and at 1 day, 4 weeks, and 8 weeks thereafter. Materials and Methods In this prospective longitudinal study (2016-2020), spectroscopic data on mI-a glial marker and osmoregulator within the brain-normalized by contralateral creatine in the intratumoral, contralateral, and peritumoral volumes of patients with recurrent GBM were evaluated. Area under the receiver operating characteristic curve (AUC) was calculated for all volumes at baseline and 1 day, 4 weeks, and 8 weeks after treatment to determine the ability of mI/c-Cr to help predict survivorship. Results Twenty-one participants (median age ± standard deviation, 62 years ± 12; 15 men) were evaluated. Lower mI/c-Cr in the tumor before and during BEV treatment was predictive of poor survivorship, with receiver operating characteristic analyses showing an AUC of 0.75 at baseline, 0.87 at 1 day after treatment, and 1 at 8 weeks after. A similar result was observed in contralateral normal-appearing tissue and the peritumoral volume, with shorter-term survivors having lower levels of mI/c-Cr. In the contralateral volume, a lower ratio of mI to creatine (hereafter, mI/Cr) predicted shorter-term survival at baseline and all other time points. Within the peritumoral volume, lower mI/c-Cr levels were predictive of shorter-term survival at baseline (AUC, 0.80), at 1 day after treatment (AUC, 0.93), and at 4 weeks after treatment (AUC, 0.68). Conclusion Lower levels of myo-inositol normalized by contralateral creatine within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and antiangiogenic treatment failure as early as before bevacizumab treatment. Adapting MR spectroscopic imaging alongside conventional MRI modalities conveys critical information regarding the biologic characteristics of tumors to help better treat individuals with recurrent glioblastoma. Clinical trial registration no. NCT02843230 © RSNA, 2021 Online supplemental material is available for this article.
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Abstract
Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and portal hypertension leads to splanchnic vasodilation, and this leads to the activation of compensatory mechanisms such as renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and antidiuretic hormone (ADH) to ameliorate low circulatory volume. The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume, resulting in the development of ascites. These compensatory mechanisms lead to impairment of the kidneys to eliminate solute-free water in decompensated cirrhosis. Nonosmotic secretion of antidiuretic hormone (ADH), also known as arginine vasopressin, further worsens excess water retention and thereby hyponatremia. The management of hyponatremia in this setting is a challenge as conventional therapies for hyponatremia including fluid restriction and correction of hypokalemia are frequently inefficacious. In this review, we discuss the pathophysiology, complications, and various treatment modalities, including albumin infusion, selective vasopressin receptor antagonists, or hypertonic saline for patients with severe hyponatremia and those awaiting liver transplantation.
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Affiliation(s)
- Joseph J. Alukal
- Institute of Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, Maryland, USA
| | - Savio John
- Division of Gastroenterology, Department of Medicine, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Paul J. Thuluvath
- Institute of Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, Maryland, USA
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Watson H, Guevara M, Vilstrup H, Ginès P. Improvement of hyponatremia in cirrhosis is associated with improved complex information processing. J Gastroenterol Hepatol 2019; 34:1999-2003. [PMID: 30965392 DOI: 10.1111/jgh.14683] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 03/21/2019] [Accepted: 04/05/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Hyponatremia, a cause of brain dysfunction and risk factor for hepatic encephalopathy, is frequent in patients with advanced cirrhosis and ascites. The interdependence of liver failure and hyponatremia makes it difficult to separate the effects of each on cognitive function. The objective was to assess whether an increase in plasma sodium in patients with cirrhosis and ascites leads to an improvement in cognitive function. METHODS This is a post-hoc analysis of 250 cirrhosis patients without overt hepatic encephalopathy randomized to receive either placebo or satavaptan, a vasopressin V2 antagonist. The exposure was plasma sodium, and the outcome was the trail-making test (TMT) parts A and B, which assesses speed of information processing, performed before the study starts and after 14 days. The results were analyzed by initial and change to final sodium concentration. RESULTS At entry, the patients with normonatremia exhibited better results on both the TMT-A (median 56 vs 77.5 s for patients with sodium ≤ 130 mmol/L [P = 0.0059]) and the TMT-B (median 127 vs 170 s for patients with sodium ≤ 130 mmol/L [P = 0.0066]), unrelated to age. Improvement of hyponatremia was more common in patients who received satavaptan (59.7%) than placebo (18.5%). Correction of hyponatremia did not shorten the simple TMT-A but markedly improved the complex TMT-B by an average of 20 s compared with 6.5 s in those with continuing hyponatremia (P = 0.02). Liver status measures remained stable during the period reported. CONCLUSIONS These data suggest that improvement of hyponatremia in patients with cirrhosis leads to an increase in the speed of complex information processing.
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Affiliation(s)
- Hugh Watson
- Infectious Diseases Research, Sanofi-Aventis R&D, Marcy l'Etoile, France.,Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark
| | - Monica Guevara
- Liver Unit, Hospital Clinic of Barcelona, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), and Centro de Investigaciones en Red Hepatologia y Digestivas (CIBEReHD), Barcelona, Spain
| | - Hendrik Vilstrup
- Department of Gastroenterology and Hepatology, Aarhus University Hospital, Aarhus, Denmark
| | - Pere Ginès
- Liver Unit, Hospital Clinic of Barcelona, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), and Centro de Investigaciones en Red Hepatologia y Digestivas (CIBEReHD), Barcelona, Spain
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Burton AG, Hopper K. Hyponatremia in dogs and cats. J Vet Emerg Crit Care (San Antonio) 2019; 29:461-471. [DOI: 10.1111/vec.12881] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 08/04/2017] [Accepted: 09/06/2017] [Indexed: 01/10/2023]
Affiliation(s)
| | - Kate Hopper
- Department of Veterinary Surgical and Radiological SciencesUniversity of California Davis CA
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Piano S, Tonon M, Angeli P. Ascites, Hyponatremia, Spontaneous Bacterial Peritonitis, and Hepatorenal Syndrome. EVIDENCE‐BASED GASTROENTEROLOGY AND HEPATOLOGY 4E 2019:662-675. [DOI: 10.1002/9781119211419.ch43] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Pathogenesis of cerebral edema in patients with acute renal and liver failure and the role of the nephrologist in the management. Curr Opin Nephrol Hypertens 2019; 27:289-297. [PMID: 29771702 DOI: 10.1097/mnh.0000000000000425] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Acute liver failure (ALF) is a severe and complex illness and one of the most daunting conditions managed in the ICU. Because the renal care is intertwined with multiple disciplines, the aim of this review is to examine the multifactorial pathogenesis of cerebral edema in ALF, covering basic established facts as well as recent advances in our understanding of this condition. RECENT FINDINGS Acetaminophen remains the most common cause of ALF in the United States and many European countries. The incidence of cerebral edema continues to decline owing to earlier detection and improved management. The pathogenesis of cerebral edema has shifted from a unifactorial hypothesis involving the failed liver to a multifactorial cause. Recent evidence focuses on the role of liver-induced systemic inflammation and its implication in increasing the permeability of the blood-brain barrier. The role of brain aquaporin-4 in mediating water entry into the brain is further clarified. Controversial data regarding the effect of acute kidney injury on the brain emerged. Hyponatremia has been shown to worsen the outcome in acute-on-chronic liver failure patients thus validating findings in animal models. New evidence shed the light on the changes in serum osmolality and potential tissue hypoxia during continuous renal replacement therapy and points to the risks associated with such therapy. SUMMARY ALF is a severe systemic illness that is potentially reversible. Understanding the interaction between the multiple failed organs will help the nephrologist provide well tolerated and efficient care.
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Bernardi M, Zaccherini G. Approach and management of dysnatremias in cirrhosis. Hepatol Int 2018; 12:487-499. [PMID: 30203382 DOI: 10.1007/s12072-018-9894-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 08/28/2018] [Indexed: 12/19/2022]
Abstract
Hypervolemic (dilutional) hyponatremia is the most common dysnatremia in cirrhosis, with a prevalence close to 50% in patients with ascites, while hypovolemic hyponatremia occurs in a minority of cases. Hyponatremia carries a poor prognosis, being associated with increased mortality and reduced survival after liver transplantation. Hypernatremia is rarer and is also associated with an adverse prognosis. Increased non-osmotic secretion of arginine vasopressin and altered renal tubular sodium handling due to impaired free water generation are the mechanisms leading to hypervolemic hyponatremia, while diuretic-induced fluid loss is the main cause of hypovolemic hyponatremia. Hypernatremia usually follows hypotonic fluid losses due to osmotic diuresis (glycosuria) or lactulose-induced diarrhea. The main clinical manifestations of dysnatremias are due to their effects on the central nervous system: astroglial cell hyperhydration follows hyponatremia-an abnormality that exacerbates ammonia neurotoxicity-while the opposite abnormality occurs with hypernatremia. Asymptomatic or mildly symptomatic hypervolemic hyponatremia is mainly managed by correcting of precipitating factors and non-osmotic fluid restriction. Severe, life-threatening hyponatremia requires hypertonic saline infusion, avoiding rapid and complete correction of serum sodium concentration to prevent neurological sequelae such as osmotic demyelination. V2 receptor blockade by vaptans may be considered in patients with sustained hyponatremia waitlisted for liver transplantation. Diuretic withdrawal and plasma volume expansion are required in hypovolemic hypernatremia. Prompt recognition, removal of the precipitating factor(s) and non-osmotic fluid administration represent the mainstays of hypernatremia management. Rapid correction of long-standing hypernatremia can lead to cerebral edema and has to be avoided.
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Affiliation(s)
- Mauro Bernardi
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Policlinico S. Orsola-Malpighi, Via Albertoni, 15, 40138, Bologna, Italy.
| | - Giacomo Zaccherini
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Policlinico S. Orsola-Malpighi, Via Albertoni, 15, 40138, Bologna, Italy
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Piano S, Tonon M, Angeli P. Management of ascites and hepatorenal syndrome. Hepatol Int 2017; 12:122-134. [DOI: 10.1007/s12072-017-9815-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 07/27/2017] [Indexed: 12/11/2022]
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Jiménez JV, Carrillo-Pérez DL, Rosado-Canto R, García-Juárez I, Torre A, Kershenobich D, Carrillo-Maravilla E. Electrolyte and Acid-Base Disturbances in End-Stage Liver Disease: A Physiopathological Approach. Dig Dis Sci 2017; 62:1855-1871. [PMID: 28501971 DOI: 10.1007/s10620-017-4597-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 04/26/2017] [Indexed: 12/17/2022]
Abstract
Electrolyte and acid-base disturbances are frequent in patients with end-stage liver disease; the underlying physiopathological mechanisms are often complex and represent a diagnostic and therapeutic challenge to the physician. Usually, these disorders do not develop in compensated cirrhotic patients, but with the onset of the classic complications of cirrhosis such as ascites, renal failure, spontaneous bacterial peritonitis and variceal bleeding, multiple electrolyte, and acid-base disturbances emerge. Hyponatremia parallels ascites formation and is a well-known trigger of hepatic encephalopathy; its management in this particular population poses a risky challenge due to the high susceptibility of cirrhotic patients to osmotic demyelination. Hypokalemia is common in the setting of cirrhosis: multiple potassium wasting mechanisms both inherent to the disease and resulting from its management make these patients particularly susceptible to potassium depletion even in the setting of normokalemia. Acid-base disturbances range from classical respiratory alkalosis to high anion gap metabolic acidosis, almost comprising the full acid-base spectrum. Because most electrolyte and acid-base disturbances are managed in terms of their underlying trigger factors, a systematic physiopathological approach to their diagnosis and treatment is required.
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Affiliation(s)
- José Víctor Jiménez
- Department of Internal Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, 14080, Mexico City, Mexico
| | - Diego Luis Carrillo-Pérez
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, 14080, Mexico City, Mexico
| | - Rodrigo Rosado-Canto
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, 14080, Mexico City, Mexico
| | - Ignacio García-Juárez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, 14080, Mexico City, Mexico
| | - Aldo Torre
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, 14080, Mexico City, Mexico
| | - David Kershenobich
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, 14080, Mexico City, Mexico
| | - Eduardo Carrillo-Maravilla
- Department of Internal Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, 14080, Mexico City, Mexico.
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Myoinositol as a Biomarker in Recurrent Glioblastoma Treated with Bevacizumab: A 1H-Magnetic Resonance Spectroscopy Study. PLoS One 2016; 11:e0168113. [PMID: 28033329 PMCID: PMC5198997 DOI: 10.1371/journal.pone.0168113] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 11/27/2016] [Indexed: 11/19/2022] Open
Abstract
Background Antiangiogenic treatment of glioblastomas with Bevacizumab lacks predictive markers. Myoinositol (MI) is an organic osmolyte, with intracellular concentration changes depending on the extracellular osmolality. Since Bevacizumab markedly reduces tumor edema and influences the tumor microenvironment, we investigated whether the MI concentration in the tumor changes during therapy. Methods We used 1H-magnetic resonance spectroscopy to measure the MI concentrations in the tumor and contralateral control tissue of 39 prospectively recruited patients with recurrent glioblastomas before and 8–12 weeks after starting therapy. 30 patients received Bevacizumab and 9 patients were treated with CCNU/VM26 as control. We performed a survival analysis to evaluate MI as a predictive biomarker for Bevacizumab therapy. Results MI concentrations increased significantly during Bevacizumab therapy in tumor (p < .001) and control tissue (p = .001), but not during CCNU/VM26 treatment. For the Bevacizumab cohort, higher MI concentrations in the control tissue at baseline (p = .021) and higher differences between control and tumor tissue (delta MI, p = .011) were associated with longer survival. A Kaplan-Meier analysis showed a median OS of 164 days for patients with a deltaMI < 1,817 mmol/l and 275 days for patients with a deltaMI > 1,817 mmol/l. No differences were observed for the relative changes or the post treatment concentrations. Additionally calculated creatine concentrations showed no differences in between subgroups or between pre and post treatment measurements. Conclusion Our data suggest that recurrent glioblastoma shows a strong metabolic reaction to Bevacizumab. Further, our results support the hypothesis that MI might be a marker for early tumor cell invasion. Pre-therapeutic MI concentrations are predictive of overall survival in patients with recurrent glioblastoma treated with Bevacizumab.
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Grover VPB, Crossey MME, Fitzpatrick JA, Saxby BK, Shaw R, Waldman AD, Morgan MY, Taylor-Robinson SD. Quantitative magnetic resonance imaging in patients with cirrhosis: a cross-sectional study. Metab Brain Dis 2016; 31:1315-1325. [PMID: 26251205 DOI: 10.1007/s11011-015-9716-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 07/26/2015] [Indexed: 12/11/2022]
Abstract
Cerebral magnetic resonance imaging was undertaken, at 3 Tesla field strength, employing magnetization transfer (MT) and diffusion-weighted imaging (DWI) sequences, in 26 patients with well-compensated cirrhosis, free of overt hepatic encephalopathy. Results were compared to those from 18 aged-matched healthy volunteers. Cerebral magnetization transfer ratios (MTR) were reduced in the frontal white matter, caudate, putamen and globus pallidus in patients with cirrhosis, compared to healthy controls, while the apparent diffusion coefficients (ADC) on DWI were significantly increased in the genu and body of the corpus callosum. An association between previous excessive alcohol consumption and both MTR and ADCs was noted, but this association was lost when controls were exercised for the severity of liver disease and psychometric impairment on multivariate analysis. Eight (31 %) of the 26 patients had impaired psychometric performance consistent with a diagnosis of minimal hepatic encephalopathy. No statistically significant difference in regional cerebral MTRs or ADCs was found in relation to neuropsychiatric status, although there was a trend towards lower MTRs in patients with impaired psychometric performance. The alterations in MTR and ADC in the patients with functionally compensated cirrhosis are compatible with theories governing the genesis of hepatic encephalopathy, including changes in astrocyte membrane permeability, with subsequent redistribution of macromolecules.
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Affiliation(s)
- Vijay P B Grover
- Liver Unit, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, 10th Floor QEQM Wing, St. Mary's Hospital Campus, South Wharf Street, London, W2 1NY, UK
- Robert Steiner MRI Unit, Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College London, London, UK
| | - Mary M E Crossey
- Liver Unit, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, 10th Floor QEQM Wing, St. Mary's Hospital Campus, South Wharf Street, London, W2 1NY, UK
| | - Julie A Fitzpatrick
- Liver Unit, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, 10th Floor QEQM Wing, St. Mary's Hospital Campus, South Wharf Street, London, W2 1NY, UK
- Robert Steiner MRI Unit, Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College London, London, UK
| | - Brian K Saxby
- Centre for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, UK
| | - Roberta Shaw
- Liver Unit, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, 10th Floor QEQM Wing, St. Mary's Hospital Campus, South Wharf Street, London, W2 1NY, UK
| | - Adam D Waldman
- Robert Steiner MRI Unit, Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College London, London, UK
| | - Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, University College London, Royal Free Campus, London, UK
| | - Simon D Taylor-Robinson
- Liver Unit, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, 10th Floor QEQM Wing, St. Mary's Hospital Campus, South Wharf Street, London, W2 1NY, UK.
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Lizaola B, Bonder A, Tapper EB, Mendez-Bocanegra A, Cardenas A. The Changing Role of Sodium Management in Cirrhosis. ACTA ACUST UNITED AC 2016; 14:274-84. [DOI: 10.1007/s11938-016-0094-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Rafat C, Flamant M, Gaudry S, Vidal-Petiot E, Ricard JD, Dreyfuss D. Hyponatremia in the intensive care unit: How to avoid a Zugzwang situation? Ann Intensive Care 2015; 5:39. [PMID: 26553121 PMCID: PMC4639545 DOI: 10.1186/s13613-015-0066-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 09/02/2015] [Indexed: 12/11/2022] Open
Abstract
Hyponatremia is a common
electrolyte derangement in the setting of the intensive care unit. Life-threatening neurological complications may arise not only in case of a severe (<120 mmol/L) and acute fall of plasma sodium levels, but may also stem from overly rapid correction of hyponatremia. Additionally, even mild hyponatremia carries a poor short-term and long-term prognosis across a wide range of conditions. Its multifaceted and intricate physiopathology may seem deterring at first glance, yet a careful multi-step diagnostic approach may easily unravel the underlying mechanisms and enable physicians to adopt the adequate measures at the patient’s bedside. Unless hyponatremia is associated with obvious extracellular fluid volume increase such as in heart failure or cirrhosis, hypertonic saline therapy is the cornerstone of the therapeutic of profound or severely symptomatic hyponatremia. When overcorrection of hyponatremia occurs, recent data indicate that re-lowering of plasma sodium levels through the infusion of hypotonic fluids and the cautious use of desmopressin acetate represent a reasonable strategy. New therapeutic options have recently emerged, foremost among these being vaptans, but their use in the setting of the intensive care unit remains to be clarified.
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Affiliation(s)
- Cédric Rafat
- AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, France. .,AP-HP, Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Paris, France.
| | - Martin Flamant
- AP-HP, Service de Physiologie Rénale, Hôpital Bichat, Paris, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,INSERM, U1149, Centre de Recherche sur l'Inflammation, Paris, France.
| | - Stéphane Gaudry
- AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,ECEVE UMR 1123, ECEVE, Paris, France.
| | - Emmanuelle Vidal-Petiot
- AP-HP, Service de Physiologie Rénale, Hôpital Bichat, Paris, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,INSERM, U1149, Centre de Recherche sur l'Inflammation, Paris, France.
| | - Jean-Damien Ricard
- AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,INSERM UMR 1137, IAME, Paris, France.
| | - Didier Dreyfuss
- AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,INSERM UMR 1137, IAME, Paris, France.
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Piano S, Morando F, Angeli P. Hyponatremia and other electrolyte/ion disorders. CIRRHOSIS: A PRACTICAL GUIDE TO MANAGEMENT 2015:199-211. [DOI: 10.1002/9781118412640.ch18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abstract
Hyponatremia is common in cirrhosis. It mostly occurs in an advanced stage of the disease and is associated with complications and increased mortality. Either hypovolemic or, more commonly, hypervolemic hyponatremia can be seen in cirrhosis. Impaired renal sodium handling due to renal hypoperfusion and increased arginine-vasopressin secretion secondary to reduced effective volemia due to peripheral arterial vasodilation represent the main mechanisms leading to dilutional hyponatremia in this setting. Patients with cirrhosis usually develop slowly progressing hyponatremia. In different clinical contexts, it is associated with neurological manifestations due to increased brain water content, where the intensity is often magnified by concomitant hyperammonemia leading to hepatic encephalopathy. Severe hyponatremia requiring hypertonic saline infusion is rare in cirrhosis. The management of asymptomatic or mildly symptomatic hyponatremia mainly rely on the identification and treatment of precipitating factors. However, sustained resolution of hyponatremia is often difficult to achieve. V2 receptor blockade by Vaptans is certainly effective, but their long-term safety, especially when associated to diuretics given to control ascites, has not been established as yet. As in other conditions, a rapid correction of long-standing hyponatremia can lead to irreversible brain damage. The liver transplant setting represents a condition at high risk for the occurrence of such complications.
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21
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Chen HJ, Chen R, Yang M, Teng GJ, Herskovits EH. Identification of minimal hepatic encephalopathy in patients with cirrhosis based on white matter imaging and Bayesian data mining. AJNR Am J Neuroradiol 2014; 36:481-7. [PMID: 25500314 DOI: 10.3174/ajnr.a4146] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND PURPOSE White matter abnormalities have been demonstrated to play an important role in minimal hepatic encephalopathy. In this study, we aimed to evaluate whether WM diffusion tensor imaging can be used to identify minimal hepatic encephalopathy among patients with cirrhosis. MATERIALS AND METHODS Our study included 65 patients with cirrhosis with covert hepatic encephalopathy (29 with minimal hepatic encephalopathy and 36 without hepatic encephalopathy). Participants underwent DTI, from which we generated mean diffusivity and fractional anisotropy maps. We used a Bayesian machine-learning technique, called Graphical-Model-based Multivariate Analysis, to determine WM regions that characterize group differences. To further test the clinical significance of these potential biomarkers, we performed Cox regression analysis to assess the potential of these WM regions in predicting survival. RESULTS In mean diffusivity or fractional anisotropy maps, 2 spatially distributed WM regions (predominantly located in the bilateral frontal lobes, corpus callosum, and parietal lobes) were consistently identified as differentiating minimal hepatic encephalopathy from no hepatic encephalopathy and yielded 75.4%-81.5% and 83.1%-92.3% classification accuracy, respectively. We were able to follow 55 of 65 patients (median = 18 months), and 15 of these patients eventually died of liver-related causes. Survival analysis indicated that mean diffusivity and fractional anisotropy values in WM regions were predictive of survival, in addition to the Child-Pugh score. CONCLUSIONS Our findings indicate that WM DTI can provide useful biomarkers differentiating minimal hepatic encephalopathy from no hepatic encephalopathy, which would be helpful for minimal hepatic encephalopathy detection and subsequent treatment.
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Affiliation(s)
- H-J Chen
- From the Jiangsu Key Laboratory of Molecular and Functional Imaging (H.-J.C., M.Y., G.-J.T.), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China Department of Radiology (H.-J.C.), The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - R Chen
- Department of Diagnostic Radiology and Nuclear Medicine (R.C., E.H.H.), University of Maryland School of Medicine, Baltimore, Maryland
| | - M Yang
- From the Jiangsu Key Laboratory of Molecular and Functional Imaging (H.-J.C., M.Y., G.-J.T.), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - G-J Teng
- From the Jiangsu Key Laboratory of Molecular and Functional Imaging (H.-J.C., M.Y., G.-J.T.), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - E H Herskovits
- Department of Diagnostic Radiology and Nuclear Medicine (R.C., E.H.H.), University of Maryland School of Medicine, Baltimore, Maryland
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Pipili C, Cholongitas E. Renal dysfunction in patients with cirrhosis: Where do we stand? World J Gastrointest Pharmacol Ther 2014; 5:156-168. [PMID: 25133044 PMCID: PMC4133441 DOI: 10.4292/wjgpt.v5.i3.156] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 02/08/2014] [Accepted: 05/08/2014] [Indexed: 02/06/2023] Open
Abstract
Patients with cirrhosis and renal failure are high-risk patients who can hardly be grouped to form precise instructions for diagnosis and treatment. When it comes to evaluate renal function in patients with cirrhosis, determination of acute kidney injury (AKI), chronic kidney disease (CKD) or AKI on CKD should be made. First it should be excluded the prerenal causes of AKI. All cirrhotic patients should undergo renal ultrasound for measurement of renal resistive index in every stage of liver dysfunction and urine microscopy for differentiation of all causes of AKI. If there is history of dehydration on the ground of normal renal ultrasound and urine microscopy the diuretics should be withdrawn and plasma volume expansion should be tried with albumin. If the patient does not respond, the correct diagnosis is HRS. In case there is recent use of nephrotoxic agents or contrast media and examination shows shock, granular cast in urinary sediment and proteinuria above 0.5 g daily, acute tubular necrosis is the prominent diagnosis. Renal biopsy should be performed when glomerular filtration rate is between 30-60 mL/min and there are signs of parenchymal renal disease. The acute renal function is preferable to be assessed with modified AKIN. Patients with AKIN stage 1 and serum creatinine ≥ 1.5 mg/dL should be at close surveillance. Management options include hemodynamic monitoring and management of fluid balance and infections, potentially driving to HRS. Terlipressin is the treatment of choice in case of established HRS, administered until there are signs of improvement, but not more than two weeks. Midodrine is the alternative for therapy continuation or when terlipressin is unavailable. Norepinephrine has shown similar effect with terlipressin in patients being in Intensive Care Unit, but with much lower cost than that of terlipressin. If the patient meets the requirements for transplantation, dialysis and transjugular intrahepatic portosystemic shunt are the bridging therapies to keep the transplant candidate in the best clinical status. The present review clarifies the latest therapeutic modalities and the proposed recommendations and algorithms in order to be applied in clinical practice.
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23
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Merola J, Chaudhary N, Qian M, Jow A, Barboza K, Charles H, Teperman L, Sigal S. Hyponatremia: A Risk Factor for Early Overt Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt Creation. J Clin Med 2014; 3:359-72. [PMID: 26237379 PMCID: PMC4449686 DOI: 10.3390/jcm3020359] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 03/04/2014] [Accepted: 03/07/2014] [Indexed: 02/07/2023] Open
Abstract
Hepatic encephalopathy (HE) is a frequent complication in cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). Hyponatremia (HN) is a known contributing risk factor for the development of HE. Predictive factors, especially the effect of HN, for the development of overt HE within one week of TIPS placement were assessed. A single-center, retrospective chart review of 71 patients with cirrhosis who underwent TIPS creation from 2006–2011 for non-variceal bleeding indications was conducted. Baseline clinical and laboratory characteristics were collected. Factors associated with overt HE within one week were identified, and a multivariate model was constructed. Seventy one patients who underwent 81 TIPS procedures were evaluated. Fifteen patients developed overt HE within one week. Factors predictive of overt HE within one week included pre-TIPS Na, total bilirubin and Model for End-stage Liver Disease (MELD)-Na. The odds ratio for developing HE with pre-TIPS Na <135 mEq/L was 8.6. Among patients with pre-TIPS Na <125 mEq/L, 125–129.9 mEq/L, 130–134.9 mEq/L and ≥135 mEq/L, the incidence of HE within one week was 37.5%, 25%, 25% and 3.4%, respectively. Lower pre-TIPS Na, higher total bilirubin and higher MELD-Na values were associated with the development of overt HE post-TIPS within one week. TIPS in hyponatremic patients should be undertaken with caution.
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Affiliation(s)
- Jonathan Merola
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
| | - Noami Chaudhary
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
| | - Meng Qian
- Department of Biostatistics, New York University School of Medicine, New York, NY 10016, USA.
| | - Alexander Jow
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
| | - Katherine Barboza
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
| | - Hearns Charles
- Department of Radiology, New York University School of Medicine, New York, NY 10016, USA.
| | - Lewis Teperman
- Department of Surgery, New York University School of Medicine, New York, NY 10016, USA.
| | - Samuel Sigal
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
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Prakoso E, Jones C, Koorey DJ, Strasser SI, Bowen D, McCaughan GW, Shackel NA. Terlipressin therapy for moderate-to-severe hyponatraemia in patients with liver failure. Intern Med J 2013; 43:240-6. [PMID: 23176166 DOI: 10.1111/imj.12032] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Accepted: 10/28/2012] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hyponatraemia in liver failure is associated with increased morbidity and mortality. Improving serum sodium in liver failure has been observed in patients receiving terlipressin. METHODS We assessed the response of hyponatraemia in patients with liver failure to terlipressin using comparative retrospective analysis. RESULTS Twenty-three patients received terlipressin for hyponatraemia after failed conservative management (median age 52 years (27-67), model for end-stage liver disease score 28 (16-38)). The median therapy was 7 days (1-27), with an average total dose of 25 mg (4-90) and a mean follow up of 51 days (5-1248). These patients were compared with 11 hyponatraemic patients managed conservatively during the same period with comparable age, baseline serum sodium and follow up. After 1 week of terlipressin therapy, serum sodium increased from a median of 120 (115-128) to 129 mmol/L (121-144) (P < 0.001), and at the end of terlipressin therapy, the serum sodium had increased significantly to 131 mmol/L (120-148) (P < 0.001). In comparison, in the conservatively managed group, the serum sodium did not increase significantly from the baseline of 123 (117-127) mmol/L. Adverse events occurred in 26% of patients receiving terlipressin, which predominantly pulmonary oedema. Importantly, more hyponatraemic patients treated with terlipressin (48%) were alive compared with the conservative group (18%), despite the latter having a significantly lower baseline median MELD score of 21 (16-30) (P = 0.008). Moreover, the transplant-free survival was higher in the terlipressin (30%) compared with the conservative group (0%). CONCLUSIONS Terlipressin is effective in treating hyponatraemia in liver failure. Importantly, terlipressin use results in better transplant-free survival but also more adverse events.
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Affiliation(s)
- E Prakoso
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, Australia
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Chacko KR, Sigal SH. Update on management of patients with overt hepatic encephalopathy. Hosp Pract (1995) 2013; 41:48-59. [PMID: 23948621 DOI: 10.3810/hp.2013.08.1068] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hepatic encephalopathy (HE) is a multifactorial neuropsychiatric disease that affects patients with cirrhosis. We review the clinical impact, pathogenesis, evaluation, management, and prevention of overt HE in patients with cirrhosis. Articles published between January 1960 and November 2012 were acquired through a MEDLINE search of different combinations of the terms hepatic encephalopathy, pathophysiology, treatment, prophylaxis, prevention, prognosis, and recurrence. The Healthcare Cost and Utilization Project database was used to obtain prevalence and cost information related to hospitalizations of patients with HE. The literature describes significant morbidity and mortality of HE in patients with cirrhosis. Overt HE develops in 30% to 45% of patients with cirrhosis and is associated with a substantial pharmacoeconomic burden, particularly HE-related hospitalizations. The development of HE in patients with cirrhosis portends a worsened prognosis and is incorporated into the Child-Pugh classification of the severity of liver disease. In the hospitalized patient, the development of HE is associated with precipitating events (eg, gastrointestinal bleeding, dehydration, infection), and in some patients, its course is characterized by frequent and severe relapses. In addition, hospitalized patients with overt HE have a 3.9-fold increased mortality risk. Patient management employs nonabsorbable disaccharides, the nonsystemic antibiotic rifaximin, or both, to treat acute HE episodes and prevent HE relapse. In open-label trials, use of the nonabsorbable disaccharide lactulose reduced the risk of overt HE recurrence in patients compared with no-lactulose control groups for ≤ a median of 14 months. In a randomized, placebo-controlled trial, rifaximin 550 mg twice daily was more effective in maintaining HE remission compared with placebo and was associated with a reduction in HE-related hospitalizations. Recent advances in treatment and preventative therapies may reduce the personal, societal, and economic impact of this disorder.
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Affiliation(s)
- Kristina R Chacko
- Division of Gastroenterology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
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Differential impact of hyponatremia and hepatic encephalopathy on health-related quality of life and brain metabolite abnormalities in cirrhosis. J Hepatol 2013; 59:467-73. [PMID: 23665182 PMCID: PMC3748234 DOI: 10.1016/j.jhep.2013.04.023] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Revised: 04/16/2013] [Accepted: 04/20/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hyponatremia (HN) and hepatic encephalopathy (HE) together can impair health-related quality of life (HRQOL) and cognition in cirrhosis. We aimed at studying the effect of hyponatremia on cognition, HRQOL, and brain MR spectroscopy (MRS) independent of HE. METHODS Four cirrhotic groups (no HE/HN, HE alone, HN alone (sodium <130 mEq/L), HE+HN) underwent cognitive testing, HRQOL using Sickness Impact Profile (SIP: higher score is worse; has psychosocial and physical sub-scores) and brain MRS (myoinositol (mI) and glutamate+glutamine (Glx)), which were compared across groups. A subset underwent HRQOL testing before/after diuretic withdrawal. RESULTS 82 cirrhotics (30 no HE/HN, 25 HE, 17 HE+HN, and 10 HN, MELD 12, 63% hepatitis C) were included. Cirrhotics with HN alone and without HE/HN had better cognition compared to HE groups (median abnormal tests no-HE/HN: 3, HN: 3.5, HE: 6.5, HE+HN: 7, p=0.008). Despite better cognition, HN only patients had worse HRQOL in total and psychosocial SIP while both HN groups (with/without HE) had a significantly worse physical SIP (p<0.0001, all comparisons). Brain MRS showed the lowest Glx in HN and the highest in HE groups (p<0.02). mI levels were comparably decreased in the three affected (HE, HE+HN, and HN) groups compared to no HE/HN and were associated with poor HRQOL. Six HE+HN cirrhotics underwent diuretic withdrawal which improved serum sodium and total/psychosocial SIP scores. CONCLUSIONS Hyponatremic cirrhotics without HE have poor HRQOL despite better cognition than those with concomitant HE. Glx levels were lowest in HN without HE but mI was similar across affected groups. HRQOL improved after diuretic withdrawal. Hyponatremia has a complex, non-linear relationship with brain Glx and mI, cognition and HRQOL.
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Watson H, Jepsen P, Wong F, Ginès P, Córdoba J, Vilstrup H. Satavaptan treatment for ascites in patients with cirrhosis: a meta-analysis of effect on hepatic encephalopathy development. Metab Brain Dis 2013; 28:301-5. [PMID: 23463488 DOI: 10.1007/s11011-013-9384-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 01/28/2013] [Indexed: 12/12/2022]
Abstract
Satavaptan, a vasopressin V2-receptor antagonist, has been shown to improve hyponatraemia in patients with cirrhosis. Hyponatraemia has been associated with an increased risk of hepatic encephalopathy. The objective is to evaluate the efficacy of satavaptan in reducing the risk of new episodes of hepatic encephalopathy. 1,200 patients with cirrhosis and uncomplicated ascites were included in three randomised double-blind studies comparing satavaptan (5-10 mg/day) vs placebo over a one-year treatment period. Effects on incidence of hepatic encephalopathy episodes in individual study and pooled databases were determined with analyses adjusted for hyponatraemia and previous episodes of encephalopathy. Hyponatraemia was improved by satavaptan. Three hundred and ninety-five hepatic encephalopathy episodes were recorded. The risk of an episode and the mean number of episodes were not reduced by satavaptan in any of the three studies in the overall population or in patients who were hyponatraemic on entry. These findings were confirmed in analysis of the pooled data. Satavaptan did not reduce the frequency of hepatic encephalopathy in patients with cirrhosis and ascites.
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Affiliation(s)
- Hugh Watson
- Sanofi R&D, 1 avenue Pierre Brossolette, 91385 Chilly-Mazarin, France.
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Overgaard-Steensen C, Ring T. Clinical review: practical approach to hyponatraemia and hypernatraemia in critically ill patients. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2013; 17:206. [PMID: 23672688 PMCID: PMC4077167 DOI: 10.1186/cc11805] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Disturbances in sodium concentration are common in the critically ill patient and associated with increased mortality. The key principle in treatment and prevention is that plasma [Na+] (P-[Na+]) is determined by external water and cation balances. P-[Na+] determines plasma tonicity. An important exception is hyperglycaemia, where P-[Na+] may be reduced despite plasma hypertonicity. The patient is first treated to secure airway, breathing and circulation to diminish secondary organ damage. Symptoms are critical when handling a patient with hyponatraemia. Severe symptoms are treated with 2 ml/kg 3% NaCl bolus infusions irrespective of the supposed duration of hyponatraemia. The goal is to reduce cerebral symptoms. The bolus therapy ensures an immediate and controllable rise in P-[Na+]. A maximum of three boluses are given (increases P-[Na+] about 6 mmol/l). In all patients with hyponatraemia, correction above 10 mmol/l/day must be avoided to reduce the risk of osmotic demyelination. Practical measures for handling a rapid rise in P-[Na+] are discussed. The risk of overcorrection is associated with the mechanisms that cause hyponatraemia. Traditional classifications according to volume status are notoriously difficult to handle in clinical practice. Moreover, multiple combined mechanisms are common. More than one mechanism must therefore be considered for safe and lasting correction. Hypernatraemia is less common than hyponatraemia, but implies that the patient is more ill and has a worse prognosis. A practical approach includes treatment of the underlying diseases and restoration of the distorted water and salt balances. Multiple combined mechanisms are common and must be searched for. Importantly, hypernatraemia is not only a matter of water deficit, and treatment of the critically ill patient with an accumulated fluid balance of 20 litres and corresponding weight gain should not comprise more water, but measures to invoke a negative cation balance. Reduction of hypernatraemia/hypertonicity is critical, but should not exceed 12 mmol/l/day in order to reduce the risk of rebounding brain oedema.
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Factors related to quality of life in patients with cirrhosis and ascites: relevance of serum sodium concentration and leg edema. J Hepatol 2012; 57:1199-206. [PMID: 22824819 DOI: 10.1016/j.jhep.2012.07.020] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Revised: 06/26/2012] [Accepted: 07/11/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Hyponatremia is common in patients with cirrhosis and ascites and is associated with significant neurological disturbances. However, its potential effect on health-related quality of life (HRQL) in cirrhosis has not been investigated. We aimed at assessing the relationship between serum sodium concentration and other clinical and analytical parameters on HRQL in cirrhosis with ascites. METHODS A total of 523 patients with cirrhosis and ascites were prospectively investigated. Assessment of HRQL was done with the Medical Outcomes Study Short-Form 36 (SF-36) questionnaire, which is divided into 8 domains, summarized in two components: physical component score (PCS) and mental component score (MCS). Demographic, clinical, and analytical data at baseline were analyzed for their relationship with HRQL. RESULTS In multivariate analysis, independent predictive factors associated with an impaired PCS were non-alcoholic etiology of cirrhosis, severe ascites, history of previous episodes of hepatic encephalopathy and falls, presence of leg edema, and low serum sodium concentration. With respect to MCS, only two factors were associated with the independent predictive value: low serum sodium concentration and treatment with lactulose or lactitol. In both components, the scores decreased in parallel with the reduction in serum sodium concentration. Variables more commonly associated with the independent predictive value in the individual 8 domains of PCS and MCS were presence of leg edema and serum sodium concentration, 7 and 6 domains, respectively. CONCLUSIONS Serum sodium concentration and presence of leg edema are major factors of the impaired HRQL in patients with cirrhosis and ascites.
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Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol 2011; 54:640-9. [PMID: 21163546 DOI: 10.1016/j.jhep.2010.07.045] [Citation(s) in RCA: 186] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2010] [Revised: 06/23/2010] [Accepted: 07/14/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Patients with cirrhosis are prone to infection which is a frequent precipitant of hepatic encephalopathy (HE). Clinical studies have examined the importance of inflammation and infection in modulating the manifestation of symptoms of HE in acute liver failure and patients with cirrhosis and minimal/low grade HE. It would be logical to presume that this relationship persists in patients who develop severe HE in cirrhosis although this has not been examined to date. METHODS We report the findings of a prospective audit of 100 consecutive patients with cirrhosis admitted between Jan 2000 and March 2008 to a liver Intensive Care Unit (ICU) where HE was the primary indication for admission (59% Grade 3; 41% Grade 4). Haematological and microbiological data were collected at ICU admission, and organ scores and outcomes were recorded. RESULTS 46% of patients had positive cultures taken within ± 48h from admission to ICU [25% blood] and a further 22% were culture negative but had evidence of systemic inflammation (SIRS). SIRS score (p=0.03) and SOFA score (p=0.006) were significantly higher in those patients with Grade 4 HE, who were also less likely to survive (p<0.001). HE grade/coma score did not correlate with ammonia, biochemistry or MELD score. Fifty-two percent of patients survived their ICU stay while the remainder developed progressive multiorgan failure and died; 38% survived to discharge, and 16% were transplanted. CONCLUSIONS These data support an association between infection/SIRS and not ammonia, in patients with cirrhosis that develop severe HE. The presence or absence of infection/SIRS did not determine survival.
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Abstract
INTRODUCTION Ascites is a common complication of advanced cirrhosis that has a significant negative impact on survival. This review updates the reader on the medical management of ascites. AREAS COVERED This review explores the pathophysiology of ascites formation in cirrhosis; the current mainstays of medical management (treating the underlying cause of cirrhosis, avoiding nephrotoxic agents, sodium restriction, and combination diuretic therapy); potential novel agents, such as vasoconstrictors and vaptans; and albumin infusions. The literature research covers all aspects of medical management of ascites from the English literature, concentrating on publications from the past 10 years. It provides a thorough understanding of how the correction of pathophysiology of ascites formation helps to improve ascites; knowledge on the monitoring of patients with cirrhosis and ascites receiving medical management, and on prophylaxis against potentially life-threatening complication such as spontaneous bacterial peritonitis; and potential new treatments for ascites. EXPERT OPINION Management of patients with cirrhosis and ascites requires careful attention to fluid and electrolyte balance and avoidance of complications. Recognition of refractory ascites allows for the use of second-line treatments. All patients with cirrhosis and ascites should be considered for liver transplantation.
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Affiliation(s)
- Wesley Leung
- University of Toronto, Toronto General Hospital, Department of Medicine, Ontario, Canada
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Abstract
UNLABELLED Hyponatremia with cerebral symptoms is a medical emergency in which treatment delay may prove fatal. However, controversy prevails over which treatment is the best. This paper presents a practical and unified approach based on a literature study of the physiology of plasma [Na(+) ], the brain's response and clinical and experimental studies. Experimental and clinical studies were thoroughly reviewed. The literature was identified through MESH and free text search in the databases PubMed, Embase and Cochrane, and references in the literature. Cerebral water homeostasis is pivotal in hyponatremia. Prompt, repeated boluses of 2 ml/kg 3% saline constitute a rational treatment of symptomatic hyponatremia. After the initial correction, concern is mainly with avoiding overcorrection and osmotic demyelination. Plasma [Na(+)] is determined by the external balances of water and cations. The water balance must therefore be carefully monitored to counter the dramatic increase in plasma [Na(+)] that may result from brisk diuresis. Definitive treatment of hyponatremia should be directed toward its etiology. This can be challenging and the clinical application of traditional classifications based on hydration is difficult. Therefore, a practical approach is proposed based on the mechanisms of impaired urine dilution. CONCLUSIONS The conflict between previously opposing standpoints is gradually giving way to an emerging consensus: Prompt bolus treatment of symptomatic hyponatremia with hypertonic saline. After the initial treatment, overcorrection must be avoided. Definitive treatment should be directed toward the nature of the underlying disorder. An approach based on the mechanism governing the impaired urine dilution has been proposed.
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Guevara M, Baccaro ME, Ríos J, Martín-Llahí M, Uriz J, Ruiz del Arbol L, Planas R, Monescillo A, Guarner C, Crespo J, Bañares R, Arroyo V, Ginès P. Risk factors for hepatic encephalopathy in patients with cirrhosis and refractory ascites: relevance of serum sodium concentration. Liver Int 2010; 30:1137-42. [PMID: 20602681 DOI: 10.1111/j.1478-3231.2010.02293.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Hyponatraemia is common in patients with advanced cirrhosis and is associated with remarkable changes in brain cells, particularly a reduction in myoinositol and other intracellular organic osmolytes related to the hypo-osmolality of the extracellular fluid. It has been recently suggested that hyponatraemia may be an important factor associated with the development of overt hepatic encephalopathy (HE). To test this hypothesis, we retrospectively analysed the incidence and predictive factors of overt HE using a database of 70 patients with cirrhosis included in a prospective study comparing transjugular intrahepatic portosystemic shunts (TIPS) vs large-volume paracentesis in the management of refractory of ascites. Variables used in the analysis included age, sex, previous history of HE, treatment assignment (TIPS vs large volume paracentesis plus albumin), treatment with diuretics, serum bilirubin, serum creatinine and serum sodium concentration. Laboratory parameters were measured at entry, at 1 month and every 3 months during follow-up and at the time of development of HE in patients who developed this complication. During a mean follow-up of 10 months, 50 patients (71%) developed 117 episodes of HE. In the whole population of patients, the occurrence of HE was independently associated with serum hyponatraemia, serum bilirubin and serum creatinine. In conclusion, in patients with refractory ascites, the occurrence of HE is related to the impairment of liver and renal function and presence of hyponatraemia.
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Affiliation(s)
- Mónica Guevara
- Liver Unit Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
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Abstract
The development of hyponatremia represents an ominous event in the progression of cirrhosis to end-stage liver disease. It usually develops in those with refractory ascites and is a manifestation of the non-osmotic release of arginine vasopressin (AVP). In the hospitalized cirrhotic patient, hyponatremia is associated with increased disease severity and mortality. In this article, we review the pathophysiology of hyponatremia, its clinical implications, evaluation, and treatment.
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Affiliation(s)
- Elizabeth Ross
- Division of Gastroenterology, Department of Medicine, New York University School of Medicine, New York, New York
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Brain volume regulation: osmolytes and aquaporin perspectives. Neuroscience 2010; 168:871-84. [DOI: 10.1016/j.neuroscience.2009.11.074] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Revised: 11/13/2009] [Accepted: 11/25/2009] [Indexed: 02/08/2023]
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Overgaard-Steensen C, Stødkilde-Jørgensen H, Larsson A, Broch-Lips M, Tønnesen E, Frøkiaer J, Ring T. Regional differences in osmotic behavior in brain during acute hyponatremia: an in vivo MRI-study of brain and skeletal muscle in pigs. Am J Physiol Regul Integr Comp Physiol 2010; 299:R521-32. [PMID: 20445159 DOI: 10.1152/ajpregu.00139.2010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Brain edema is suggested to be the principal mechanism underlying the symptoms in acute hyponatremia. Identification of the mechanisms responsible for global and regional cerebral water homeostasis during hyponatremia is, therefore, of utmost importance. To examine the osmotic behavior of different brain regions and muscles, in vivo-determined water content (WC) was related to plasma sodium concentration ([Na(+)]) and brain/muscle electrolyte content. Acute hyponatremia was induced with desmopressin acetate and infusion of a 2.5% glucose solution in anesthetized pigs. WC in different brain regions and skeletal muscle was estimated in vivo from T(1) maps determined by magnetic resonance imaging (MRI). WC, expressed in gram water per 100 g dry weight, increased significantly in slices of the whole brain [342(SD = 14) to 363(SD = 21)] (6%), thalamus [277(SD = 13) to 311(SD = 24)] (12%) and white matter [219(SD = 7) to 225(SD = 5)] (3%). However, the WC increase in the whole brain and white mater WC was less than expected from perfect osmotic behavior, whereas in the thalamus, the water increase was as expected. Brain sodium content was significantly reduced. Muscle WC changed passively with plasma [Na(+)]. WC determined with deuterium dilution and tissue lyophilzation correlated well with MRI-determined WC. In conclusion, acute hyponatremia induces brain and muscle edema. In the brain as a whole and in the thalamus, regulatory volume decrease (RVD) is unlikely to occur. However, RVD may, in part, explain the observed lower WC in white matter. This may play a potential role in osmotic demyelination.
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Abstract
Hyponatremia is a common problem in patients with advanced cirrhosis. Hyponatremia in cirrhosis includes two distinct types: hypovolemic hyponatremia, and hypervolemic or dilutional hyponatremia. The former is characterized by low blood sodium, low blood volume, dehydration and prerenal renal dysfunction, not accompanied by edema and ascites, while the latter is characterized by insufficient circulatory volume and dilutional hyponatremia, accompanied by edema and ascites. Hyponatremia is closely related to various complications of cirrhosis and to early mortality after liver transplantation. Vaptans, a class of selective non-peptide arginine vasopressin (AVP) receptor antagonists, act by antagonizing specifically the effects of AVP V2 receptor located in the renal collecting tubules to inhibit water reabsorption without affecting electrolytes excretion. Vaptans has been evaluated by several clinical trials for their role in the management of hyponatremia. The short-term treatment with vaptans is associated with a marked increase in renal solute-free water excretion and improvement of hyponatremia with no apparent adverse reactions. The discovery of vaptans is considered a new milestone in the management of hyponatremia in cirrhosis.
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Hyponatremia in cirrhosis answers and questions. J Clin Gastroenterol 2010; 44:157-8. [PMID: 19935084 DOI: 10.1097/mcg.0b013e3181c21b27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
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Córdoba J, García-Martinez R, Simón-Talero M. Hyponatremic and hepatic encephalopathies: similarities, differences and coexistence. Metab Brain Dis 2010; 25:73-80. [PMID: 20217202 DOI: 10.1007/s11011-010-9172-3] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Accepted: 11/27/2009] [Indexed: 12/11/2022]
Abstract
Hyponatremic and hepatic encephalopathy are common causes of metabolic encephalopathy that may coexist in patients with cirrhosis. The clinical picture is common to any metabolic encephalopathy and is characterized by a confusional syndrome that may evolve into coma. Chronic mild or minimal manifestations can be seen in both, but motor symptoms are more common in hepatic encephalopathy. Recent advances show that in addition to clinical manifestations both encephalopathies share some pathogenetic mechanisms. Dysfunction of astrocytes, osmotic changes in the brain and brain edema are present in both situations. Recognition of these abnormalities is important to plan therapy. New drugs that affect brain hydration may be useful for both encephalopathies.
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Affiliation(s)
- Juan Córdoba
- Servei de Medicina Interna-Hepatologia, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119, Barcelona, 08035, Spain.
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Heins J, Zwingmann C. Organic osmolytes in hyponatremia and ammonia toxicity. Metab Brain Dis 2010; 25:81-9. [PMID: 20195726 DOI: 10.1007/s11011-010-9170-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2009] [Accepted: 01/28/2010] [Indexed: 01/06/2023]
Abstract
Hyperammonemia (HA) is a major and commonly observed feature of hepatic encephalopathy. Furthermore, hyponatremia is an important pathogenetic factor in patients with hepatic encephalopathy. Both conditions have some features in common, such as the release of organic osmolytes, which might be an adaptive mechanism against cell swelling. However, the consequence of a possible relationship between osmoregulatory response in hyperammonemia and hyponatremia is not completely understood. This review gives a short introduction into the pathogenesis of hepatic encephalopathy and hyponatremia. For a comparison of both pathological events, some basics on cellular osmo- and volume regulation are explained, in particular as the mechanisms involved in the adaption of the cell to volume changes can be different under both pathological conditions. The role of brain glutamine and organic osmolytes in hyponatremia and hyperammonemia and their combination are discussed based on findings in experimental animal models, and finally on data obtained from primary astrocytes in culture. The observations that the decrease of brain organic osmolytes in astrocytes not adequately compensate for an increased intracellular osmolarity caused by glutamine are consistent with results obtained after chronic hyponatremia in rats, in which the release of osmolytes does not protect from ammonia-induced brain edema. Furthermore, a decrease in intracellular osmolarity is attributed both to the release and a reduced de novo synthesis of amino acids.
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Affiliation(s)
- Jessica Heins
- Département de médicine, Centre de Recherche Hôpital Saint-Luc, Université de Montréal, 264, René Lévesque Est, Montréal, Quebec, Canada, H2X 1P1
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Sharma P, Sharma BC, Sarin SK. Predictors of nonresponse to lactulose for minimal hepatic encephalopathy in patients with cirrhosis. Liver Int 2009; 29:1365-71. [PMID: 19555401 DOI: 10.1111/j.1478-3231.2009.02067.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND/AIMS Minimal hepatic encephalopathy (MHE) impairs health-related quality of life and predicts overt hepatic encephalopathy (HE) in cirrhotic patients. Lactulose is effective in the treatment of MHE. However, not all patients respond to lactulose. We evaluated predictors of nonresponse to lactulose. PATIENTS AND METHODS Consecutive 110 cirrhotic patients without HE were evaluated for MHE by psychometry, P300 auditory event-related potential (P300ERP), venous ammonia and critical flicker frequency (CFF). MHE was diagnosed by abnormal psychometry and P300ERP (>2 SD). MHE patients were treated with lactulose for 1 month. Response was defined by normalization of the abnormal test parameters (both psychometric tests and P300ERP). RESULTS Sixty patients (54.5%) were diagnosed as having MHE: 17/39 (44%) in Child's A, 21/42 (50%) Child's B and 22/29 (76%) in Child's C. There was a significant difference between Child's C's vs Child's A's and B's (P<0.05). Abnormal psychometric tests and abnormal P300ERP were seen in 74 (67%) and 74 (67%) patients respectively. Of 60 patients with MHE, after treatment, psychometry remained abnormal in 22 (36.6%) and P300ERP in 21 (35%) patients. CFF was<38 Hz in 34 (57%) and 11 (18%) patients, respectively, before and after treatment in MHE patients. There was a significant difference between the baseline serum sodium level (134.7+/-2.6 vs 131.1+/-2.2 mmol/L, P=0.001) and the venous ammonia level (76.6+/-20.7 vs 113.4+/-22.8 micromol/L, P=0.001) between responders vs nonresponders. Receiver operating characteristic analysis was performed to identify the cutoff for venous ammonia [cutoff 93.5 mmol/L, area under the curve (AUC) 0.892 (0.814-0.970)] and for the serum sodium level [cutoff 132.5 mmol/L, AUC 0.874 (0.779-0.998)]. Taking a cutoff of 93.5 mmol/L for ammonia patient had a sensitivity of 88.5% and a specificity of 79.4%, respectively, and a cutoff of 132.5 mmol/L for serum sodium patient had a sensitivity of 76.5% and a specificity of 88.5% for nonresponse to lactulose. On univariate analysis and multivariate analysis, serum sodium and venous ammonia were the only two parameters associated with nonresponse to lactulose. CONCLUSION The prevalence of MHE was 55% and MHE improved in 57% patients with lactulose. Baseline low serum sodium and high venous ammonia were highly predictive of nonresponse to lactulose therapy.
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Affiliation(s)
- Praveen Sharma
- Department of Gastroenterology, G. B. Pant Hospital, New Delhi, India
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Hackworth WA, Heuman DM, Sanyal AJ, Fisher RA, Sterling RK, Luketic VA, Shiffman ML, Maluf DG, Cotterell AH, Posner MP, Stravitz RT. Effect of hyponatraemia on outcomes following orthotopic liver transplantation. Liver Int 2009; 29:1071-7. [PMID: 19302181 DOI: 10.1111/j.1478-3231.2009.01982.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hyponatraemia increases risk of adverse outcomes following orthotopic liver transplantation (OLT), but it is unclear whether improvement of pretransplant hyponatraemia ameliorates post-transplant complications. AIMS To assess impact of pretransplant hyponatraemia on post-transplant outcomes. METHODS We performed a retrospective analysis of 213 patients with cirrhosis who underwent liver transplantation. Patients with serum sodium <or=130 mEq/L immediately before transplantation ('hyponatraemia at OLT'; n=34) were compared with those who had experienced hyponatraemia but subsequently improved to a serum sodium >130 mEq/L at transplantation ('resolved hyponatraemia'; n=56) and to those without history of hyponatraemia before transplantation ('never hyponatraemic'; n=123). Primary endpoint was survival at 180 days post-OLT. Secondary outcomes included time until discharge alive, complications during hospitalization, length of time ventilated and length of post-transplant intensive care unit stay. RESULTS There was no survival difference at 180 days post-OLT between groups. After transplantation, patients with either hyponatraemia at OLT or resolved hyponatraemia had longer time until discharge alive and had higher rates of delirium, acute renal failure, acute cellular rejection and infection than those who were never hyponatraemic. As compared with patients with hyponatraemia at OLT, those with resolved hyponatraemia were more likely to be discharged alive within 3 weeks, but other outcomes, including survival, did not differ significantly. CONCLUSIONS We conclude that hyponatraemia at any time before liver transplantation is associated with adverse post-transplant outcome, even when hyponatraemia has resolved.
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Affiliation(s)
- William A Hackworth
- Liver Transplant Program, Hume-Lee Transplant Center, Virginia Commonwealth University Medical Center, Richmond, VA, USA
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Davies NA, Wright G, Ytrebø LM, Stadlbauer V, Fuskevåg OM, Zwingmann C, Davies DC, Habtesion A, Hodges SJ, Jalan R. L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats. Hepatology 2009; 50:155-64. [PMID: 19437490 DOI: 10.1002/hep.22897] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
UNLABELLED Treatment of hyperammonemia and hepatic encephalopathy in cirrhosis is an unmet clinical need. The aims of this study were to determine whether L-ornithine and phenylacetate/phenylbutyrate (administered as the pro-drug phenylbutyrate) (OP) combined are synergistic and produce sustained reduction in ammonia by L-ornithine acting as a substrate for glutamine synthesis, thereby detoxifying ammonia, and the phenylacetate excreting the ornithine-derived glutamine as phenylacetylglutamine in the urine. Sprague-Dawley rats were studied 4 weeks after bile duct ligation (BDL) or sham operation. Study 1: Three hours before termination, an internal carotid sampling catheter was inserted, and intraperitoneal saline (placebo), OP, phenylbutyrate, or L-ornithine were administered after randomization. BDL was associated with significantly higher arterial ammonia and brain water and lower brain myoinositol (P < 0.01, respectively), compared with sham-operated controls, which was significantly improved in the OP-treated animals; arterial ammonia (P < 0.001), brain water (P < 0.05), brain myoinositol (P < 0.001), and urinary phenylacetylglutamine (P < 0.01). Individually, L-ornithine or phenylbutyrate were similar to the BDL group. In study 2, BDL rats were randomized to saline or OP administered intraperitoneally for 6 hours or 3, 5, or 10 days and were sacrificed between 4.5 and 5 weeks. The results showed that the administration of OP was associated with sustained reduction in arterial ammonia (P < 0.01) and brain water (P < 0.01) and markedly increased arterial glutamine (P < 0.01) and urinary excretion of phenylacetylglutamine (P < 0.01) in each of the OP treated groups. CONCLUSION The results of this study provide proof of the concept that L-ornithine and phenylbutyrate/phenylacetate act synergistically to produce sustained improvement in arterial ammonia, its brain metabolism, and brain water in cirrhotic rats.
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Affiliation(s)
- Nathan A Davies
- Liver Failure Group, Institute of Hepatology, University College London, UK
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Garcia-Tsao G, Lim JK. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program. Am J Gastroenterol 2009; 104:1802-1829. [PMID: 19455106 DOI: 10.1038/ajg.2009.191] [Citation(s) in RCA: 170] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cirrhosis represents the end stage of any chronic liver disease. Hepatitis C and alcohol are currently the main causes of cirrhosis in the United States. Although initially cirrhosis is compensated, it eventually becomes decompensated, as defined by the presence of ascites, variceal hemorrhage, encephalopathy, and/or jaundice. These management recommendations are divided according to the status, compensated or decompensated, of the cirrhotic patient, with a separate section for the screening, diagnosis, and management of hepatocellular carcinoma (HCC), as this applies to patients with both compensated and decompensated cirrhosis. In the compensated patient, the main objective is to prevent variceal hemorrhage and any practice that could lead to decompensation. In the decompensated patient, acute variceal hemorrhage and spontaneous bacterial peritonitis are severe complications that require hospitalization. Hepatorenal syndrome is also a severe complication of cirrhosis but one that usually occurs in patients who are already in the hospital and, as it represents an extreme of the hemodynamic alterations that lead to ascites formation, it is placed under treatment of ascites. Recent advances in the pathophysiology of the complications of cirrhosis have allowed for a more rational management of cirrhosis and also for the stratification of patients into different risk groups that require different management. These recommendations are based on evidence in the literature, mainly from randomized clinical trials and meta-analyses of these trials. When few or no data exist from well-designed prospective trials, emphasis is given to results from large series and consensus conferences with involvement of recognized experts. A rational management of cirrhosis will result in improvements in quality of life, treatment adherence, and, ultimately, in outcomes.
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Kim JH, Lee JS, Lee SH, Bae WK, Kim NH, Kim KA, Moon YS. The association between the serum sodium level and the severity of complications in liver cirrhosis. Korean J Intern Med 2009; 24:106-12. [PMID: 19543488 PMCID: PMC2698618 DOI: 10.3904/kjim.2009.24.2.106] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2008] [Accepted: 09/22/2008] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND/AIMS Dilutional hyponatremia associated with liver cirrhosis is caused by impaired free water clearance. Several studies have shown that serum sodium levels correlate with survival in cirrhotic patients. Little is known, however, regarding the relationship between the degree of dilutional hyponatremia and development of cirrhotic complications. The aim of this study was to evaluate the association between the serum sodium level and the severity of complications in liver cirrhosis. METHODS Data of inpatients with cirrhotic complications were collected retrospectively. The serum sodium levels and severity of complications of 188 inpatients were analyzed. RESULTS The prevalence of dilutional hyponatremia, classified as serum sodium concentrations of <or=135 mmol/L, <or=130 mmol/L, and <or=125 mmol/L, were 20.8%, 14.9%, and 12.2%, respectively. The serum sodium level was strongly associated with the severity of liver function impairment as assessed by Child-Pugh and MELD scores (p<0.0001). Even a mild hyponatremia with a serum sodium concentration of 131-135 mmol/L was associated with severe complications. Sodium levels less than 130 mmol/L indicated the existence of massive ascites (OR, 2.685; CI, 1.316-5.477; p=0.007), grade III or higher hepatic encephalopathy (OR, 5.891; CI, 1.490-23.300; p=0.011), spontaneous bacterial peritonitis (OR, 2.562; CI, 1.162-5.653; p=0.020), and hepatic hydrothorax (OR, 5.723; CI, 1.889-17.336; p=0.002). CONCLUSIONS Hyponatremia, especially serum levels <or=130 mmol/L, may indicate the existence of severe complications associated with liver cirrhosis.
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Affiliation(s)
- Jong Hoon Kim
- Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - June Sung Lee
- Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Seuk Hyun Lee
- Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Won Ki Bae
- Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Nam-Hoon Kim
- Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Kyung-Ah Kim
- Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Young-Soo Moon
- Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
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Abstract
Hyponatremia, a common complication inpatients with advanced liver disease and impaired free water clearance, has been shown to be an important predictor of short-term mortality. Hepatic encephalopathy, also a late complication of end-stage liver disease, has been associated with low-grade cerebral edema as a result of swelling of astrocytes. Guevara et al. hypothesized that hyponatremia and the resultant depletion of organic osmolytes (e.g.,myo-inositol) from brain cells contribute to brain edema, playing an important role in the pathogenesis of hepatic encephalopathy. Using a multivariable analysis, they demonstrated that hyponatremia increased the risk of hepatic encephalopathy more than eightfold, after adjustment for serum bilirubin and creatinine concentrations and previous history of encephalopathy. Their magnetic resonance spectroscopy data correlated low brain concentrations of myoinositol with hepatic encephalopathy. As both hyponatremia and encephalopathy occur in patients with advanced liver disease, it has been difficult to implicate hyponatremia independently in the pathogenesis of hepatic encephalopathy. Guevara's data do suggest that hyponatremia is more likely an accomplice than an innocent bystander.
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Guevara M, Baccaro ME, Torre A, Gómez-Ansón B, Ríos J, Torres F, Rami L, Monté-Rubio GC, Martín-Llahí M, Arroyo V, Ginès P. Hyponatremia is a risk factor of hepatic encephalopathy in patients with cirrhosis: a prospective study with time-dependent analysis. Am J Gastroenterol 2009; 104:1382-9. [PMID: 19455124 DOI: 10.1038/ajg.2009.293] [Citation(s) in RCA: 158] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The aim of this study was to investigate whether hyponatremia is a risk factor of overt hepatic encephalopathy (HE) in cirrhosis. METHODS A total of 61 patients with cirrhosis were evaluated prospectively for 1 year and all episodes of overt HE were recorded. Predictive factors of HE were analyzed using a conditional model (Prentice, Williams, and Peterson) for recurrent events to assess the relationship between HE and time-dependent covariates. The effects of hyponatremia on the brain concentration of organic osmolytes were analyzed in 25 patients using 1 H-magnetic resonance spectroscopy. RESULTS Twenty-eight of the 61 patients developed 57 episodes of overt HE during follow-up. Among a number of clinical and laboratory variables analyzed, the only independent predictive factors of overt HE were hyponatremia (serum sodium < 130 mEq / l), history of overt HE, serum bilirubin,and serum creatinine. Hyponatremia was associated with low brain concentration of organic osmolytes, particularly myo-inositol (MI). Furthermore, patients with low brain MI levels had a higher probability of development of overt HE compared with that of patients with high brain MI levels. CONCLUSIONS In patients with cirrhosis, the existence of hyponatremia is a major risk factor of the development of overt HE. Treatment of hyponatremia may be a novel therapeutic approach to preventing HE in cirrhosis.
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Affiliation(s)
- Mónica Guevara
- Liver Unit, Hospital Clinic, University of Barcelona, Villarroel 170, Barcelona, Spain.
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Zahr NM, Mayer D, Vinco S, Orduna J, Luong R, Sullivan EV, Pfefferbaum A. In vivo evidence for alcohol-induced neurochemical changes in rat brain without protracted withdrawal, pronounced thiamine deficiency, or severe liver damage. Neuropsychopharmacology 2009; 34:1427-42. [PMID: 18704091 PMCID: PMC2669706 DOI: 10.1038/npp.2008.119] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Magnetic resonance spectroscopy (MRS) studies in human alcoholics report decreases in N-acetylaspartate (NAA) and choline-containing (Cho) compounds. Whether alterations in brain metabolite levels are attributable to alcohol per se or to physiological effects of protracted withdrawal or impaired nutritional or liver status remains unclear. Longitudinal effects of alcohol on brain metabolites measured in basal ganglia with single-voxel MRS were investigated in sibling pairs of wild-type Wistar rats, with one rat per pair exposed to escalating doses of vaporized alcohol, the other to vapor chamber air. MRS was conducted before alcohol exposure and twice during exposure. After 16 weeks of alcohol exposure, rats achieved average blood alcohol levels (BALs) of approximately 293 mg per 100 ml and had higher Cho and a trend for higher glutamine+glutamate (Glx) than controls. After 24 weeks of alcohol exposure, BALs rose to approximately 445 mg per 100 ml, and alcohol-exposed rats had higher Cho, Glx, and glutamate than controls. Thiamine and thiamine monophosphate levels were significantly lower in the alcohol than the control group but did not reach levels low enough to be considered clinically relevant. Histologically, livers of alcohol-exposed rats exhibited greater steatosis and lower glycogenosis than controls, but were not cirrhotic. This study demonstrates a specific pattern of neurobiochemical changes suggesting excessive membrane turnover or inflammation, indicated by high Cho, and alterations to glutamate homeostasis in the rat brain in response to extended vaporized alcohol exposure. Thus, we provide novel in vivo evidence for alcohol exposure as causing changes in brain chemistry in the absence of protracted withdrawal, pronounced thiamine deficiency, or severe liver damage.
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Affiliation(s)
- Natalie M Zahr
- Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA, Neuroscience Program, SRI International, Menlo Park, CA, USA
| | - Dirk Mayer
- Neuroscience Program, SRI International, Menlo Park, CA, USA, Radiology Department, Lucas MRS/I Center, Stanford University, Stanford, CA, USA
| | - Shara Vinco
- Neuroscience Program, SRI International, Menlo Park, CA, USA
| | - Juan Orduna
- Neuroscience Program, SRI International, Menlo Park, CA, USA
| | - Richard Luong
- Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Edith V Sullivan
- Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA,Correspondence: Dr EV Sullivan, Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305-5723, USA, Tel: + 1 650 859 2880, Fax: + 1 650 859 2743, E-mail:
| | - Adolf Pfefferbaum
- Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA, Neuroscience Program, SRI International, Menlo Park, CA, USA
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Córdoba Cardona J. La encefalopatía hepática hoy: cómo la incertidumbre mantiene algunas inercias clínicas. Med Clin (Barc) 2009; 132:425-7. [DOI: 10.1016/j.medcli.2008.10.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2008] [Accepted: 10/14/2008] [Indexed: 10/20/2022]
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Shawcross DL, Wright GAK, Stadlbauer V, Hodges SJ, Davies NA, Wheeler-Jones C, Pitsillides AA, Jalan R. Ammonia impairs neutrophil phagocytic function in liver disease. Hepatology 2008; 48:1202-12. [PMID: 18697192 DOI: 10.1002/hep.22474] [Citation(s) in RCA: 132] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED Hyperammonemia is a feature of liver failure, which is associated with increased risk of infection. The aims of the present study were to determine in vitro, in rats fed an ammoniagenic diet and in patients with cirrhosis, whether induction of hyperammonemia results in neutrophil dysfunction. As hyperammonemia produces cell swelling, we explored the role of the osmoregulating, p38 mitogen-activated protein kinase (p38(MAPK)) pathway in mediating this neutrophil dysfunction. Neutrophils were isolated from blood of healthy volunteers and incubated with either 75 microM ammonia or phosphate-buffered saline. Both groups were studied under hyponatremic conditions and/or with the addition of p38(MAPK) modulators. Neutrophil phagocytosis was measured in naive rats and rats fed an ammoniagenic diet and in patients with stable cirrhosis given placebo (n = 8) or an amino acid solution inducing hyperammonemia (n = 8). Cell volume and phagocytosis was analyzed by fluorescent-activated cell sorting using fluorescein isothiocyanate-labeled E. coli. p38(MAPK) phosphorylation was measured by western blotting. In healthy neutrophils incubated with ammonia and in rats fed an ammoniagenic diet, neutrophils showed evidence of swelling, impaired phagocytosis, and increased spontaneous oxidative burst compared to controls. Phagocytosis was significantly impaired in patients with induced hyperammonemia compared to placebo. The effects of hyperammonemia and hyponatremia were synergistic. The p38(MAPK) intracellular signaling pathways were activated in healthy neutrophils exposed to ammonia in association with increased burst activity. Neutrophil phagocytic dysfunction was abrogated by the addition of a p38(MAPK) agonist. CONCLUSION Ammonia produces neutrophil swelling and impairs neutrophil phagocytosis. The p38(MAPK) intracellular signaling pathway has been shown to be important in mediating the ammonia-induced neutrophil dysfunction.
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Affiliation(s)
- Debbie L Shawcross
- Liver Failure Group, The University College London (UCL) Institute of Hepatology, Division of Medicine, University College London, London, UK
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