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Protopapas AA, Tsankof A, Papagiouvanni I, Kaiafa G, Skoura L, Savopoulos C, Goulis I. Outpatient management after hospitalisation for acute decompensation of cirrhosis: A practical guide. World J Hepatol 2024; 16:1377-1394. [PMID: 39744202 PMCID: PMC11686542 DOI: 10.4254/wjh.v16.i12.1377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 10/24/2024] [Accepted: 11/20/2024] [Indexed: 11/29/2024] Open
Abstract
Acute decompensation in cirrhotic patients signifies the onset of clinically evident events due to portal hypertension. The transition from compensated to decompensated cirrhosis involves hemodynamic changes leading to multiorgan dysfunction, managed predominantly in outpatient settings with regular monitoring. The mortality risk is elevated in decompensated patients. Therefore, diligent outpatient management should focus on regular medical follow-ups, medication adjustments, patient education, addressing emergent issues and evaluation for liver transplantation. The ultimate goal is to improve quality of life, prevent disease progression, reduce complications, and assess possible recompensation. This guide provides valuable recommendations for medical experts managing decompensated cirrhotic patients post-hospitalization.
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Affiliation(s)
- Adonis A Protopapas
- First Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 54636, Greece.
| | - Alexandra Tsankof
- First Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Ioanna Papagiouvanni
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Georgia Kaiafa
- First Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Lemonia Skoura
- Department of Microbiology, Aristotle University οf Thessaloniki, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Christos Savopoulos
- First Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Ioannis Goulis
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
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Gao Y, Liu X, Gao Y, Duan M, Hou B, Chen Y. Pharmacological Interventions for Cirrhotic Ascites: From Challenges to Emerging Therapeutic Horizons. Gut Liver 2024; 18:934-948. [PMID: 39205495 PMCID: PMC11565010 DOI: 10.5009/gnl240038] [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: 01/23/2024] [Revised: 05/01/2024] [Accepted: 05/02/2024] [Indexed: 09/04/2024] Open
Abstract
Ascites is the most common complication in patients with decompensated cirrhosis. This condition results in a severely impaired quality of life, excessive healthcare use, recurrent hospitalizations and significant morbidity and mortality. While loop diuretics and mineralocorticoid receptor antagonists are commonly employed for symptom relief, our understanding of their impact on survival remains limited. A comprehensive understanding of the underlying pathophysiological mechanism of ascites is crucial for its optimal management. The renin-angiotensin-aldosterone system (RAAS) is increasingly believed to play a pivotal role in the formation of cirrhotic ascites, as RAAS overactivation leads to a reduction in urine sodium excretion then a decrease in the ability of the kidneys to excrete water. In this review, the authors provide an overview of the pathogenesis of cirrhotic ascites, the challenges associated with current pharmacologic treatments, and the previous attempts to modulate the RAAS, followed by a description of some emerging targeted RAAS agents with the potential to be used to treat ascites.
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Affiliation(s)
- Yuan Gao
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xin Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yunyi Gao
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Meili Duan
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Bing Hou
- Xenorm MedInfo Center, Beijing, China
| | - Yu Chen
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
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Seidita A, Mandreucci F, Pistone M, Calderone S, Giuliano A, Chiavetta M, Giannitrapani L, Citarrella R, Soresi M, Licata A, Carroccio A, Compagnoni S. Sodium-glucose cotransporter 2 inhibition in patients with liver cirrhosis and diabetes: a possible role in ascites control? ITALIAN JOURNAL OF MEDICINE 2024; 18. [DOI: 10.4081/itjm.2024.1829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
Abstract
The aim of this brief report is to evaluate sodium-glucose cotransporter 2 inhibitors (SGLT2-I) effects on patients with both refractory ascites and type 2 diabetes mellitus (T2D). We consecutively recruited all the diabetic patients with refractory ascites due to decompensated liver cirrhosis admitted between February and May 2023 at the Internal Medicine Unit of the University Hospital of Palermo. Clinical and laboratory data were collected after starting SGLT2-I therapy. SGLT2-I use was associated with a reduction/resolution of ascites and with an improvement in serum albumin and sodium levels and estimated glomerular filtration rate. SGLT2-I might represent a valid therapeutic option in the treatment of patients with refractory ascites and T2D, as already hypothesized by other research groups.
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Ambery P, Greasley PJ, Menzies RI, Brynne L, Kulkarni S, Oscarsson J, Davenport AP. Targeting the endothelium by combining endothelin-1 antagonism and SGLT-2 inhibition: better together? Clin Sci (Lond) 2024; 138:687-697. [PMID: 38835256 DOI: 10.1042/cs20240605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/17/2024] [Accepted: 05/22/2024] [Indexed: 06/06/2024]
Abstract
Endothelin A and B receptors, together with sodium-glucose cotransporter-2 (SGLT-2) channels are important targets in improving endothelial function and intervention with inhibitors has been the subject of multiple mechanistic and clinical outcome trials over recent years. Notable successes include the treatment of pulmonary hypertension with endothelin receptor antagonists, and the treatment of heart failure and chronic kidney disease with SGLT-2 inhibitors. With distinct and complementary mechanisms, in this review, we explore the logic of combination therapy for a number of diseases which have endothelial dysfunction at their heart.
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Affiliation(s)
- Phil Ambery
- Clinical Late Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Peter J Greasley
- Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Robert I Menzies
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Lena Brynne
- Information Practice Late Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Spoorthy Kulkarni
- Department of Clinical Pharmacology and Therapeutics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB20QQ, U.K
- Division of Experimental Medicine and Immunotherapeutics, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K
| | - Jan Oscarsson
- Clinical Late Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Anthony P Davenport
- Division of Experimental Medicine and Immunotherapeutics, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K
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Wu HHL, Rakisheva A, Ponnusamy A, Chinnadurai R. Hepatocardiorenal syndrome in liver cirrhosis: Recognition of a new entity? World J Gastroenterol 2024; 30:128-136. [PMID: 38312119 PMCID: PMC10835518 DOI: 10.3748/wjg.v30.i2.128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/05/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Emerging evidence and perspectives have pointed towards the heart playing an important role in hepatorenal syndrome (HRS), outside of conventional understanding that liver cirrhosis is traditionally considered the sole origin of a cascade of pathophysiological mechanisms directly affecting the kidneys in this context. In the absence of established heart disease, cirrhotic cardiomyopathy may occur more frequently in those with liver cirrhosis and kidney disease. It is a specific form of cardiac dysfunction characterized by blunted contractile responsiveness to stress stimuli and altered diastolic relaxation with electrophysiological abnormalities. Despite the clinical description of these potential cardiac-related complications of the liver, the role of the heart has traditionally been an overlooked aspect of circulatory dysfunction in HRS. Yet from a physiological sense, temporality (prior onset) of cardiorenal interactions in HRS and positive effects stemming from portosystemic shunting demonstrated an important role of the heart in the development and progression of kidney dysfunction in cirrhotic patients. In this review, we discuss current concepts surrounding how the heart may influence the development and progression of HRS, and the role of systemic inflammation and endothelial dysfunction causing circulatory dysfunction within this setting. The temporality of heart and kidney dysfunction in HRS will be discussed. For a subgroup of patients who receive portosystemic shunting, the dynamics of cardiorenal interactions following treatment is reviewed. Continued research to determine the unknowns in this topic is anticipated, hopefully to further clarify the intricacies surrounding the liver-heart-kidney connection and improve strategies for management.
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Affiliation(s)
- Henry H L Wu
- Renal Research, Kolling Institute of Medical Research, Royal North Shore Hospital & The University of Sydney, St. Leonards (Sydney) 2065, New South Wales, Australia
| | - Amina Rakisheva
- Department of Cardiology, City Cardiological Center, Almaty 050000, Kazakhstan
| | - Arvind Ponnusamy
- Department of Renal Medicine, Royal Preston Hospital, Preston PR2 9HT, United Kingdom
| | - Rajkumar Chinnadurai
- Donal O’Donoghue Renal Research Centre & Department of Renal Medicine, Northern Care Alliance National Health Service Foundation Trust, Salford M6 8HD, United Kingdom
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Jensen ASH, Ytting H, Winther-Sørensen M, Burisch J, Bergquist A, Gluud LL, Wewer Albrechtsen NJ. Autoimmune liver diseases and diabetes. Eur J Gastroenterol Hepatol 2023; 35:938-947. [PMID: 37505973 DOI: 10.1097/meg.0000000000002594] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/30/2023]
Abstract
Autoimmune liver diseases include autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. They are chronic, heterogenous diseases affecting the liver which is a key metabolic organ that ensures glucose homeostasis. It is well known that patients with other chronic liver diseases such as cirrhosis and nonalcoholic fatty liver disease (NAFLD) display glucose disturbances like insulin resistance and have an increased risk of diabetes. Previous evidence on glucose disturbances in patients with autoimmune liver disease is scarce but does point towards a potentially increased risk of type 1 diabetes and type 2 diabetes. The underlying mechanisms are unknown but may reflect genetic predisposition, concurrent NAFLD and or cirrhosis development, and treatment (steroid) related impairment of glucose homeostasis. Therefore, increased awareness and surveillance of diabetes development in patients with autoimmune liver disease may be important. Overall, detection and treatment of diabetes generally follow the usual diabetes guidelines; however, in patients with advanced liver cirrhosis, HbA1c may not be a reliable marker of average glucose levels, and treatment with insulin is generally recommended. In addition, it has recently been suggested that sodium-glucose cotransporter 2 inhibitors may be beneficial in treating refractory ascites. Further research on diabetes risk in autoimmune liver disease is warranted.
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Affiliation(s)
- Anne-Sofie H Jensen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
| | - Henriette Ytting
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Rigshospitalet
- Institute for Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen
| | - Marie Winther-Sørensen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
| | - Johan Burisch
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
| | - Annika Bergquist
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
- Department of Upper GI Diseases, Karolinska University Hospital, Department of Medicine, Karolinska Institutet, Stockholm
| | - Lise Lotte Gluud
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
- Institute for Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen
| | - Nicolai J Wewer Albrechtsen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
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Brankovic M, Lee P, Pyrsopoulos N, Klapholz M. Cardiac Syndromes in Liver Disease: A Clinical Conundrum. J Clin Transl Hepatol 2023; 11:975-986. [PMID: 37408802 PMCID: PMC10318294 DOI: 10.14218/jcth.2022.00294] [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: 06/14/2022] [Revised: 09/28/2022] [Accepted: 11/28/2022] [Indexed: 07/03/2023] Open
Abstract
Understanding the interaction between the heart and liver is pivotal for managing patients in whom both organs are affected. Studies have shown that cardio-hepatic interactions are bidirectional and that their identification, assessment, and treatment remain challenging. Congestive hepatopathy is a condition that develops in the setting of long-standing systemic venous congestion. If left untreated, congestive hepatopathy may lead to hepatic fibrosis. Acute cardiogenic liver injury develops as a combination of venous stasis and sudden arterial hypoperfusion due to cardiac, circulatory, or pulmonary failure. The treatment of both conditions should be directed toward optimizing the cardiac substrate. Hyperdynamic syndrome may develop in patients with advanced liver disease and lead to multiorgan failure. Cirrhotic cardiomyopathy or abnormalities in pulmonary vasculature, such as hepatopulmonary syndrome and portopulmonary hypertension may also develop. Each complication has unique treatment challenges and implications for liver transplantation. The presence of atrial fibrillation and atherosclerosis in liver disease brings another layer of complexity, particularly in terms of anticoagulation and statin use. This article provides an overview of cardiac syndromes in liver disease, focusing on current treatment options and future perspectives.
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Affiliation(s)
- Milos Brankovic
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
- Transatlantic Cardiovascular Study Group, Bloomfield, NJ, USA
| | - Paul Lee
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Nikolaos Pyrsopoulos
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Mark Klapholz
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
- Division of Cardiology, Heart Failure Prevention and Treatment Program, Rutgers New Jersey Medical School, Newark, NJ, USA
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Wong F. Innovative approaches to the management of ascites in cirrhosis. JHEP Rep 2023; 5:100749. [PMID: 37250493 PMCID: PMC10220491 DOI: 10.1016/j.jhepr.2023.100749] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 02/20/2023] [Accepted: 03/15/2023] [Indexed: 05/31/2023] Open
Abstract
Standard of care for the treatment of ascites in cirrhosis is to administer a sodium-restricted diet and diuretic therapy. The progression of cirrhosis will eventually lead to the development of refractory ascites, at which point diuretics will no longer be able to control the ascites. Second-line therapies such as a transjugular intrahepatic portosystemic shunt (TIPS) placement or repeat large volume paracentesis are then required. There is some evidence that regular infusions of albumin may delay the onset of refractoriness and improve survival, especially if given at an early stage in the natural history of ascites and for a long enough duration. The use of TIPS can eliminate ascites, but its insertion is associated with complications, especially cardiac decompensation and worsening of hepatic encephalopathy. New information is now available regarding how to best select patients for TIPS, what type of cardiac investigations are needed and how under-dilating the TIPS at the time of insertion may help. The use of a non-absorbable antibiotics, such as rifaximin, starting in the pre-TIPS period may also reduce the likelihood of post-TIPS hepatic encephalopathy. In patients who are not suitable for TIPS, the use of an alfapump to remove the ascites via the bladder can improve quality of life without significantly altering survival. In the future it may be possible to use metabolomics to help refine the management of patients with ascites, e.g. to assess their response to non-selective beta-blockers or to predict the development of other complications such as acute kidney injury.
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Affiliation(s)
- Florence Wong
- Department of Medicine, Division of Gastroenterology & Hepatology, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Patoulias D, Michailidis T. SGLT-2 Inhibitor and GLP-1 Receptor Agonist Treatment for Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Is Their Combination the Optimal Treatment Option? J Clin Transl Hepatol 2022; 10:574-576. [PMID: 36062276 PMCID: PMC9396330 DOI: 10.14218/jcth.2022.00278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 06/16/2022] [Accepted: 06/22/2022] [Indexed: 12/04/2022] Open
Affiliation(s)
- Dimitrios Patoulias
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital “Hippokration,” Thessaloniki, Greece
- Correspondence to: Dimitrios Patoulias, Second Propedeutic Department of Internal Medicine, General Hospital “Hippokration,” Konstantinoupoleos 49, 54642, Thessaloniki, Greece. ORCID: https://orcid.org/0000-0002-6899-684X. Tel: +30-6946900777, Fax: +30-2310225083, E-mail:
| | - Theodoros Michailidis
- Second Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital “Hippokration,” Thessaloniki, Greece
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Koufakis T, Mustafa OG, Ajjan RA, Garcia-Moll X, Zebekakis P, Dimitriadis G, Kotsa K. From Skepticism to Hope: The Evolving Concept of the Initiation and Use of Sodium-Glucose Cotransporter 2 Inhibitors in Hospitalized Patients. Drugs 2022; 82:949-955. [PMID: 35678922 PMCID: PMC9178534 DOI: 10.1007/s40265-022-01730-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2022] [Indexed: 01/10/2023]
Abstract
The management of hyperglycemia in patients admitted to hospital is mainly based on insulin therapy. However, the positive and rapid effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiorenal outcomes raises the possibility that they might confer benefits to hospitalized patients. In recent, well designed, randomized trials (SOLOIST-WHF and EMPULSE) recruiting inpatients with heart failure (HF), SGLT2i demonstrated the potential to improve survival and quality of life and reduce the number of HF events, time to first HF event, hospitalizations, and urgent visits for HF compared with placebo. They were also well tolerated, whereas incidence of diabetic ketoacidosis was low. In EMBODY, empagliflozin was shown to be protective against the deleterious effects of cardiac injury in patients with acute myocardial infarction. In DARE-19, the administration of dapagliflozin to inpatients with cardiometabolic risk factors and COVID-19 was based on the hypothesis that the anti-inflammatory properties of SGLT2i could alleviate organ damage. Although the findings did not reach statistical significance, the efficacy and safety profiles of the drug were encouraging. These promising findings in the field of cardiometabolic medicine set the stage for future research to explore whether the benefits of gliflozins can expand to inpatients with non-cardiometabolic disorders, including sepsis, cirrhotic ascites, and malignancies. The concept of inpatient use of SGLT2i has evolved greatly over the past few years. The latest evidence suggests that SGLT2i may be effective and safe in the hospital setting, provided patients are carefully selected and closely monitored. Real-world data will prove whether present hope about inpatient use of gliflozins will transform into future confidence.
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Affiliation(s)
- Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece
| | - Omar G Mustafa
- Department of Diabetes, King's College Hospital, London, UK
| | - Ramzi A Ajjan
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds Ringgold Standard Institution, Leeds, UK
| | - Xavier Garcia-Moll
- Cardiology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma, 91 Mas Casanova, 08041, Barcelona, Spain
| | - Pantelis Zebekakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece
| | - George Dimitriadis
- Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece.
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