Endocrinology
Series Editors
Andrea�Lenzi
Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy
Emmanuele�A.�Jannini
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

Series Editor:Lenzi , Andrea; Series Co-Editor:Jannini , Emmanuele A.

Within the health sciences, Endocrinology has an unique and pivotal role. This old, but continuously new science is the study of the various hormones and their actions and disorders in the body. The matter of Endocrinology are the glands, i.e. the organs that produce hormones, active on the metabolism, reproduction, food absorption and utilization, growth and development, behavior control, and several other complex functions of the organisms. Since hormones interact, affect, regulate and control virtually all body functions, Endocrinology not only is a very complex science, multidisciplinary in nature, but is one with the highest scientific turnover.

Knowledge in the Endocrinological sciences is continuously changing and growing. In fact, the field of Endocrinology and Metabolism is one where the highest number of scientific publications continuously flourishes. The number of scientific journals dealing with hormones and the regulation of body chemistry is dramatically high. Furthermore, Endocrinology is directly related to genetics, neurology, immunology, rheumatology, gastroenterology, nephrology, orthopedics, cardiology, oncology, gland surgery, psychology, psychiatry, internal medicine, and basic sciences. All these fields are interested in updates in Endocrinology.

More information about this series at http://?www.?springer.?com/?series/?14021 The aim of the MRW in Endocrinology is to update the Endocrinological matter using the knowledge of the best experts in each section of Endocrinology: basic endocrinology, neuroendocrinology, endocrinological oncology, pancreas with diabetes and other metabolic disorders, thyroid, parathyroid and bone metabolism, adrenals and endocrine hypertension, sexuality, reproduction, and behavior.

Editors
Piero�Portincasa, Gema�Fr�hbeck and Hendrik�M.�Nathoe

Endocrinology and Systemic Diseases

1st ed. 2021
With 48 Figures and 20 Tables
Editors
Piero�Portincasa
Department of Biomedical Sciences and Human Oncology, University of Bari ?Aldo Moro?, Clinica Medica ?Augusto Murri?, Bari, Italy
Gema�Fr�hbeck
Department of Endocrinology & Nutrition, University of Navarra, CIBEROBN, IdiSNA, Clinica Universidad de Navarra, Pamplona, Spain
Hendrik�M.�Nathoe
Department of Cardiology, University Medical Center, Utrecht, The Netherlands
ISSN 2510-1927e-ISSN 2510-1935
Endocrinology
ISBN 978-3-319-68728-5e-ISBN 978-3-319-68729-2
� Springer Nature Switzerland AG 2021
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG.

The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Series Preface

Is there an unmet need for a new MRW series in Endocrinology and Metabolism? It might not seem so! The vast number of existing textbooks, monographs and scientific journals suggest that the field of hormones (from genetic, molecular, biochemical and translational to physiological, behavioral, and clinical aspects) is one of the largest in biomedicine, producing a simply huge scientific output. However, we are sure that this new series will be of interest for scientists, academics, students, physicians and specialists alike.

The knowledge in Endocrinology and Metabolism limited to the two main (from an epidemiological perspective) diseases, namely hypo/hyperthyroidism and diabetes mellitus, now seems outdated and perhaps closer to the practical interests of the general practitioner than to those of the specialist. This has led to endocrinology and metabolism being increasingly considered as a subsection of internal medicine rather than an autonomous specialization. But endocrinology is much more than this. We are proposing this series as the manifesto for Endocrinology 2.0, embracing the fields of medicine in which hormones play a major part but which, for various historical and cultural reasons, have thus far been ?ignored? by endocrinologists. Hence, this MRW comprises ?traditional? (but no less important or investigated) topics: from the molecular actions of hormones to the pathophysiology and management of pituitary, thyroid, adrenal, pancreatic and gonadal diseases, as well as less usual and common arguments. Endocrinology 2.0 is, in fact, the science of hormones, but it is also the medicine of sexuality and reproduction, the medicine of gender differences and the medicine of well-being. These aspects of Endocrinology have to date been considered of little interest, as they are young and relatively unexplored sciences. But this is no longer the case. The large scientific production in these fields coupled with the impressive social interest of patients in these topics is stimulating a new and fascinating challenge for Endocrinology.

The aim of the MRW in Endocrinology is thus to update the subject with the knowledge of the best experts in each field: basic endocrinology, neuroendocrinology, endocrinological oncology, pancreatic disorders, diabetes and other metabolic disorders, thyroid, parathyroid and bone metabolism, adrenal and endocrine hypertension, sexuality, reproduction and behavior. We are sure that this ambitious aim, covering for the first time the whole spectrum of Endocrinology 2.0, will be fulfilled in this vast Springer MRW in Endocrinology Series.

Andrea�Lenzi
Emmanuele�A.�Jannini
Volume Preface

Endocrinology and Systemic Diseases combines common aspects of clinical endocrinology with major topics of internal medicine and provides a comprehensive outlook of the complex and bi-directional relationship between hormonal homeostasis and a variety of organ dysfunctions.

The editors are fully aware of the exponential expansion of knowledge in biomedicine, which requires continuous multidisciplinary approaches across specialists, disciplines, health policies, and established evidence-based guidelines. On the other hand, the risk deriving from overspecialization could lead to the lack of an integrative approach, increasing diagnosis mistakes and health costs.

The daily need of individual practitioners is to address multiple, complex, and often overlapping diagnoses, available diagnostic and therapeutic capacities, confounding subclinical manifestations, cross-links between dysfunctions in different systems, and integration of single cases with ongoing guidelines in a rapidly evolving scientific knowledge.

In this first edition, experts at the forefront of knowledge in their specific fields focus on the multifactorial mechanisms linking endocrinological disorders and systemic abnormalities, which include liver and gastrointestinal diseases; heart and cardiovascular diseases; kidney, autoimmune, neuroendocrine and rheumatic disorders; neurological and psychiatric manifestations; critically ill conditions; elderly patients; and dermatological diseases. Because of close attention to the role of environment on human health, a chapter also deals with the role of environmental pollution in endocrine diseases.

This first edition of Endocrinology and Systemic Diseases therefore intercepts the rapid change of knowledge in endocrine aspects of clinical medicine and provides a useful tool to adequately manage the altered hormonal balance frequently linked with several clinical conditions.

We trust that the book will be helpful and informative, and therefore will support and improve the continuous medical education of trainees and MD specialists, for a full management of complex clinical cases.

We thank all authors who contributed with both enthusiasm and dedication to the impact of the book.

Clinica Medica ?A. Murri?, Department of Biomedical Sciences and Human Oncology Prof. Piero Portincasa

University of Bari Medical School

Bari, Italy

Senior Consultant of Department of Endocrinology and Nutrition Prof Gema Fr�hbeck

University Clinic of Navarra CIBEROBN, Avda. Pio XII, 36

Pamplona, Spain

University Medical Center Utrecht Prof. Hendrik M. Nathoe

Utrecht, The Netherlands Editors

January 2021
Contents
Federico�Carbone, Aldo�Bonaventura, Alessandra�Vecchi�, Matteo�Casula, Luca�Liberale, Franco�Dallegri and Fabrizio�Montecucco
Marcel�Th.�B.�Twickler, Jakub�Regieli, Remco�Grobben, Einar�A.�Hart, Margot�E.�Tesselaar, Ronald�C.�A.�Meijer, Steven�A.�J.�Chamuleau and Hendrik�M.�Nathoe
Federico�Carbone, Aldo�Bonaventura, Luca�Liberale, Alessandra�Vecchi�, Matteo�Casula, Franco�Dallegri and Fabrizio�Montecucco
Silvia�Matino, Francesco�Pesce, Michele�Rossini, Giuseppina�D?Ettorre, Alessandro�Mascolo and Loreto�Gesualdo
Agostino�Di Ciaula, Grigorios�Christidis, Marcin�Krawczyk, Frank�Lammert and Piero�Portincasa
Agostino�Di Ciaula, David�Q.�H.�Wang, Thomas�Sommers, Antony�Lembo and Piero�Portincasa
Hagit�Peleg and Eldad�Ben-Chetrit
Maurizio�Cutolo and Amelia�Chiara�Trombetta
Pablo�Irimia Sieira, Ane�M�nguez Olaondo, Eduardo�Mart�nez-Vila and Martin�Ruttledge
Javier�Salvador, Gala�Gutierrez, Mar�a�Llavero, Javier�Gargallo, Javier�Escalada and Judith�L�pez
Gabriella�Garruti, Ana�F.�Pina, M.�Paula�Machedo and Francesco�Giorgino
P.�Sunsundegui, V.�Santesteban-Moriones and M.�F.�Landecho
Domenico�Bonamonte and Angela�Filoni
Agostino�Di Ciaula and Piero�Portincasa
Index 467
Editors and Contributors
About the Editors
Piero�Portincasa
../images/441013_1_En_BookFrontmatter_Figb_HTML.jpg

(M.D., Ph.D. [Utrecht], dr. H. Causa) is Full Professor of Internal Medicine and Chief of the Academic Division of Internal Medicine ?A. Murri,? Department of Biomedical Sciences and Human Oncology at the University ?Aldo Moro? Medical School and of the Unit of Internal Medicine ?A. Pende,? Regional Hospital Policlinico in Bari, Italy. He is director of the 4-year residency program in geriatrics. The activities as internist, teacher, and scientist combine both basic and clinical research in the field of dyslipidaemia and metabolic disorders, liver steatosis and gallstone disease, and rare autoinflammatory diseases (Familial Mediterranean Fever). His teaching and research group deals with aspects of food digestion and intolerances, gastrointestinal motility, and application of standard and novel diagnostic tests in gastrointestinal and liver diseases. He is author of more than 500 international papers and several books and chapters.

Prof. Portincasa worked as University Research Fellow at Guy?s Hospital, London, UK (1985?87); as Clinician and Ph.D. student at the Academic Hospital in Utrecht, the Netherlands (1993?95); and as Clinical Fellow of the National Research Centre (CNR) at Harvard Medical School, Beth Israel Deaconess Medical Centre, Boston, USA (2005). He served as Councillor of the European Society for Clinical Investigation, ESCI (2008?11), President of ESCI (2011?15), President of Foundation of European Journal of Clinical Investigation (2015?18), and since 2018 is President of ESCI Trust. He was the organizer of the 2010 Annual scientific Meeting of ESCI in Bari and he will organize again the next ESCI meeting in 2021, in Bari. Prof. Portincasa holds the Laurea H. Causa at the Universities ?C. Davila,? Bucharest (2013), ?Iuliu Hatieganu? Cluj-Napoca (2013), and ?George Emil Palade? Targu-Mures (2018), Romania. He is member of the Apulian Academy of Sciences, past Councillor and Secretary (2013?17) of the Italian Society Internal Medicine, and recipient of the prestigious ESCI Albert Struyvenberg Medal in 2018. He also holds the Fellowship of the American Gastroenterological Association (AGAF). Prof. Portincasa is active in international relations as Erasmus+ coordinator in Bari and worldwide as member of several international scientific societies and journal editorial boards. He is mentoring undergraduate and postgraduate students of medicine, biology, and pharmacy also involved in the Horizon 2020 Foie Gras project.

Gema�Fr�hbeck
../images/441013_1_En_BookFrontmatter_Figc_HTML.jpg

(RNutr, M.D., Ph.D.) combines everyday work in the clinical setting as Director of the Obesity Area and Senior Consultant in the Department of Endocrinology and Nutrition at the Cl�nica Universidad de Navarra (Pamplona, Spain) with basic research as Head of the Metabolic Research Laboratory at the University of Navarra and Project Leader of CIBEROBN (Centre of Excellence Network in Obesity and Nutrition of the Spanish Institute of Health). Her group has taken the step forward of routinely using body composition measurements in the clinical assessment of patients in order to analyze the relevance of body fat ? beyond body mass index ? in comorbidity development. In 1997, she worked as Postdoctoral Fellow of the Royal Society in Prof. Andrew Prentice?s Energy Group at the MRC Dunn Clinical Nutrition Centre in Cambridge, UK. In 2009, she was unanimously voted President-Elect of the European Association for the Study of Obesity. Prof. Fr�hbeck is also a recipient of the Nutrition Society?s Silver Medal, UK (2000), ?Sir David Cuthbertson Medal? (2005), Lilly Distinguished Career Award in Endocrinology and Nutrition (2011), and Albert Struyvenberg Medal (2013). From 2012 to 2015 Prof. Fr�hbeck served as President of the European Association for the Study of Obesity. She has also served as Councillor of the European Society for Clinical Investigation (2014?2018).

Hendrik�M.�Nathoe
../images/441013_1_En_BookFrontmatter_Figd_HTML.jpg

was born in Surinam, South America, and moved to the Netherlands in 1983.

He studied medicine at the Erasmus Medical Center Rotterdam and graduated summa cum laude in 1991. Prof. Nathoe received his Ph.D. degree in 2004 from the University of Utrecht under supervision of Prof. Diederick Grobbee and Prof. Peter de Jaegere His thesis was entitled Coronary revascularization: Stent-implantation, on-pump or off-pump bypass surgery.

After his training he was appointed in 2006 at the University Medical Center Utrecht as General Cardiologist and Associate Professor of Cardiology.

Since 2018, he has been Medical Head of the Center for Cardiovascular Disease, the care facility of the UMC Utrecht research focus ?Circulatory Health?. Here, he collaborates with other vascular specialists to optimize the care of multidisciplinary vascular patients. In 2019, this center was accredited as one of the first in Europe by the European Society of Cardiology for primary and secondary prevention and sports medicine.

Since 2020, he has been appointed as Medical Head of the outpatient clinic in the Department of Cardiology at UMC Utrecht.

Prof. Nathoe was involved in the governance of the European Society for Clinical Investigation (ESCI) since 2013 as Secretary Treasurer and President. He organized the annual scientific meeting of ESCI in 2014 in Utrecht.

He (co)-authored 125 peer-reviewed articles of whom one as first author in the New England Journal of Medicine. He supervised 6 Ph.D. students.

He is member of many steering committees such as SMART study, CHASE investigators, Octopus study, BEACON trial, DECS study, and MARC study.

Prof. Nathoe was involved in the 2019 European Society of Cardiology guidelines on ?the management of chronic coronary syndromes.?

Since 2020, he is Editor-in-Chief of the European Journal of Clinical Investigation.

Contributors
Eldad�Ben-Chetrit
Rheumatology Unit, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Domenico�Bonamonte
Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, Bari, Italy
Aldo�Bonaventura
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Federico�Carbone
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Matteo�Casula
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Steven�A.�J.�Chamuleau
University Medical Center Utrecht, Utrecht, The Netherlands
Grigorios�Christidis
Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
Maurizio�Cutolo
Research Laboratory and Clinical Division of Rheumatology, Department of Internal Medicine, University of Genova, IRCCS San Martino Polyclinic Hospital, Genova, Italy
Giuseppina�D?Ettorre
Department of Emergency and Organ Transplantation (DETO), Nephrology, Dialysis and Kidney Transplantation Unit, University of Bari ?Aldo Moro?, Bari, Italy
Franco�Dallegri
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
IRCCS Ospedale Policlinico San Martino ? Italian Cardiovascular Network, Genoa, Italy
Agostino�Di Ciaula
Clinica Medica ?A. Murri?, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
Division of Internal Medicine, Hospital of Bisceglie (BAT), ASL BAT, Bisceglie, Italy
International Society of Doctors for Environment ? ISDE, Basel, Switzerland
Javier�Escalada
Department of Endocrinology and Nutrition, University Clinic of Navarra, Pamplona, Spain
CIBERObn, Institute Carlos III, Madrid, Spain
Angela�Filoni
Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, Bari, Italy
Javier�Gargallo
Department of Endocrinology and Nutrition, University Clinic of Navarra, Pamplona, Spain
Gabriella�Garruti
Section of Internal Medicine, Endocrinology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Medical School, Bari, Italy
Loreto�Gesualdo
Department of Emergency and Organ Transplantation (DETO), Nephrology, Dialysis and Kidney Transplantation Unit, University of Bari ?Aldo Moro?, Bari, Italy
Francesco�Giorgino
Section of Internal Medicine, Endocrinology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Medical School, Bari, Italy
Remco�Grobben
University Medical Center Utrecht, Utrecht, The Netherlands
Gala�Gutierrez
Department of Endocrinology and Nutrition, University Clinic of Navarra, Pamplona, Spain
Einar�A.�Hart
University Medical Center Utrecht, Utrecht, The Netherlands
Pablo�Irimia Sieira
Departamento de Neurolog�a, Cl�nica Universidad de Navarra, Pamplona, Spain
Marcin�Krawczyk
Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
Frank�Lammert
Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
M.�F.�Landecho
General Health Check-up Unit, Internal Medicine Department, Cl�nica Universidad de Navarra, Pamplona, Spain
Antony�Lembo
Division of Gastroenterology, Beth Israel and Deaconess Center, Harvard Medical School, Boston, MA, USA
Luca�Liberale
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Center for Molecular Cardiology, University of Z�rich, Schlieren, Switzerland
Mar�a�Llavero
Department of Endocrinology and Nutrition, University Clinic of Navarra, Pamplona, Spain
Judith�L�pez
Department of Endocrinology and Nutrition, University Hospital of Canarias and University of La Laguna, Tenerife, Spain
Ane�M�nguez Olaondo
Departamento de Neurolog�a, Cl�nica Universidad de Navarra, Pamplona, Spain
M.�Paula�Machedo
Chronic Diseases Research Center, NOVA Medical School/Faculdade de Ci�ncias M�dicas, Universidade Nova de Lisboa, Lisbon, Portugal
Eduardo�Mart�nez-Vila
Departamento de Neurolog�a, Cl�nica Universidad de Navarra, Pamplona, Spain
Alessandro�Mascolo
Department of Emergency and Organ Transplantation (DETO), Nephrology, Dialysis and Kidney Transplantation Unit, University of Bari ?Aldo Moro?, Bari, Italy
Silvia�Matino
Department of Emergency and Organ Transplantation (DETO), Nephrology, Dialysis and Kidney Transplantation Unit, University of Bari ?Aldo Moro?, Bari, Italy
Ronald�C.�A.�Meijer
Department of Cardiothoracic Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands
Fabrizio�Montecucco
Ospedale Policlinico San Martino, Genoa, Italy
First Clinic of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), Department of Internal Medicine, University of Genoa, Genoa, Italy
IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Nework, Genoa, Italy
Hendrik�M.�Nathoe
Department of Cardiology, University Medical Center, Utrecht, The Netherlands
Hagit�Peleg
Rheumatology Unit, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
M.�Perticone
Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy
F.�Perticone
Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
Francesco�Pesce
Department of Emergency and Organ Transplantation (DETO), Nephrology, Dialysis and Kidney Transplantation Unit, University of Bari ?Aldo Moro?, Bari, Italy
Ana�F.�Pina
Chronic Diseases Research Center, NOVA Medical School/Faculdade de Ci�ncias M�dicas, Universidade Nova de Lisboa, Lisbon, Portugal
Piero�Portincasa
Department of Biomedical Sciences and Human Oncology, University of Bari ?Aldo Moro?, Clinica Medica ?Augusto Murri?, Bari, Italy
Jakub�Regieli
Private cardiology clinic, Amsterdam, The Netherlands
Michele�Rossini
Department of Emergency and Organ Transplantation (DETO), Nephrology, Dialysis and Kidney Transplantation Unit, University of Bari ?Aldo Moro?, Bari, Italy
Martin�Ruttledge
Neurology Department, Beaumont Hospital, Dublin 9, Ireland
Javier�Salvador
Department of Endocrinology and Nutrition, University Clinic of Navarra, Pamplona, Spain
CIBERObn, Institute Carlos III, Madrid, Spain
V.�Santesteban-Moriones
General Health Check-up Unit, Internal Medicine Department, Cl�nica Universidad de Navarra, Pamplona, Spain
Department of Endocrinology and Nutrition, Cl�nica Universidad de Navarra, Pamplona, Spain
Department of Nutrition, Food Sciences and Physiology, University of Navarra, Pamplona, Spain
Centre for nutrition research, University of Navarra, Pamplona, Spain
CIBER fisiopatologia de la obesidad y nutrici�n (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
Thomas�Sommers
Division of Gastroenterology, Beth Israel and Deaconess Center, Harvard Medical School, Boston, MA, USA
P.�Sunsundegui
General Health Check-up Unit, Internal Medicine Department, Cl�nica Universidad de Navarra, Pamplona, Spain
Margot�E.�Tesselaar
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Amelia�Chiara�Trombetta
Research Laboratory and Clinical Division of Rheumatology, Department of Internal Medicine, University of Genova, IRCCS San Martino Polyclinic Hospital, Genova, Italy
Marcel�Th.�B.�Twickler
Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital, Edegem, Belgium
AZ Monica, Antwerp/Deurne, Belgium
Alessandra�Vecchi�
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
David�Q.�H.�Wang
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA