Hydro Saline Metabolism: Epidemiology, Genetics, Pathophysiology, Diagnosis and Treatment (Endocrinology)

This book provides an overview of endocrine diseases associated with alterations of salt metabolism, with a focus on clinical and pathophysiological aspects. It covers various topics in the endocrine control of salt and water homeostasis, such as neuroendocrine determinants of water balance, adrenal hormone biosynthesis, hormonal function in target renal cells, and dysfunction of hormonal target effectors in the kidney. It also features an update on the clinical management of these diseases, including new diagnostic and therapeutic tools. Written by a combination of recognized and emerging experts in the field, this book is intended as a major reference work, not only for endocrinologists and nephrologists, but also for pediatricians, neonatologists, cardiologists, and emergency medicine and intensive care specialists, who can be faced with the management of endocrine diseases responsible of salt and water imbalance. The book is part of the SpringerReference program, which provides access to ‘living editions’ that are constantly updated using a dynamic, peer-review publishing process. Series Preface Volume Preface Contents About the Editors Contributors 1 Neuroendocrine Regulation of Hydrosaline Metabolism Introduction Historical Background: The Pioneer Studies From Sensors to Effector Systems The Control of Extracellular Fluid Osmolality The Control of Extracellular Fluid Volume Integrating Brain, Heart, and Kidneys The Renin-Angiotensin-Aldosterone System Natriuretic Peptides Integrated Autonomic Control of Cardiovascular System and Hydromineral Balance Novel Local Players on the Control of Hypothalamic Function Gaseous Modulators Endocannabinoids Glial Cells From Fetal Life to Senescence: The Neuroendocrine Regulation of Hydromineral Balance During the Life Span Fetal Programming Sex-Related Differences Aging Exercise Conclusion References 2 Physiology of Vasopressin Secretion Introduction Anatomy of the Neurohypophysis Synthesis and Release Circulating Vasopressin and Degradation Regulation of Vasopressin Release Osmoregulation and Thirst Baroregulation Vasopressin Release During Pregnancy Receptors and Actions V1 Receptor V2 Receptor V3 Receptor Conclusions References 3 Tubulopathies and Alterations of the RAAS Introduction Mechanisms of NaCl Reabsorption in the Renal Tubule Mechanisms of NaCl reabsorption in each Renal Tubule Segment Proximal Tubule Thick Ascending Limb Distal Convoluted Tubule Collecting Duct Diseases Associated with RAAS Activation Salt-losing Tubulopathies of Renal Proximal Tubule Salt-losing Tubulopathies of the Thick Ascending Limb Salt-losing Tubulopathies of the Distal Convoluted Tubule Salt-losing Tubulopathies of the Collecting Duct Salt-losing Mixed Tubulopathy Diseases Associated with RAAS Inactivation Liddle Syndrome Apparent Mineralocorticoid Excess Conclusion References 4 Familial Hyperkalemic Hypertension (FHHt) Introduction From Familial Hyperkalemic Hypertension to the Discovery of New Regulators of Ion Handling by the Distal Nephron Clinical Aspects of Familial Hyperkalemic Hypertension A Quick Tour of Na+ Reabsorption and K+ Secretion by the Distal Nephron At Least Four Genes Implicated in Familial Hyperkalemic Hypertension (FHHt) Regulation of NCC Phosphorylation by WNK1 Isoforms and WNK4 The WNK Family of Serine-Threonine Kinases SPAK and OSR1 - Key Players of Cation-Chloride Cotransporters Activation Identification of SPAK and OSR1 SPAK Is Essential for the Phosphorylation and Activity of NCC Activation of SPAK and NCC by WNKs L-WNK1 Activates NCC Independently of WNK4 WNK4 Is an Activator of SPAK The WNK1-SPAK-NCC Cascade Is Modulated by Extracellular Potassium A WNK Network to Modulate NCC The CUL3-KLHL3 Complex Modulates the Abundance of WNK Kinases The CUL3/KLHL3 Complex KLHL3 and CUL3 Regulate WNKs Ubiquitination and Degradation Involvement of the CUL3-Ubiquitin Ligase Complex in the Physiological Regulation of the WNK Pathway in the DCT Mutations in Any of the Four ``FHHt Genes ́ ́ Result in an Increased Abundance of WNK4 and/or WNK1 Isoforms KLHL3 Mutations Prevent the Recruitment of the Substrate or the Binding to CUL3 CUL3 Mutations Disturb the Activity of the Ubiquitin Ligase Complex WNK4 Mutations Prevent Its Ubiquitination Two Types of Mutations in WNK1 for Two Different Renal Syndromes Increased Expression of L-WNK1 Triggers the Development of FHHt An Increased Abundance of KS-WNK1 Results in Hyperkalemic Metabolic Acidosis The Pathophysiology of FHHt CUL3-Dependent FHHt Is a Renal and Vascular Disease Is FHHt Solely Caused by an Increased Activity of NCC? Is ENaC Regulated by L-WNK1 and WNK4? Is ROMK Regulated by L-WNK1 and WNK4? β-Intercalated Cells: A Partner of DCT Cells to Trigger FHHt? Activation of SPAK in DCT Cells Is Sufficient to Induce the Development of FHHt Are ``FHHt Genes ́ ́ Involved in the Pathogenesis of Essential Hypertension? Identification of Polymorphisms and Variants Associated with a Higher Risk of Hypertension in the General Population Can the Inhibition of SPAK, OSR1 and/or WNKs Be Considered as a Relevant Anti-Hypertensive Strategy? Conclusion References 5 Diabetes Insipidus: Novel Diagnostic Approaches Introduction Etiology Clinical Presentation Diagnosis Confirmation of the Hypotonic Polyuria Differential Diagnosis Within the Polyuria-Polydipsia Syndrome Water Deprivation Test Direct Testing and Copeptin Assessment Tests to Predict CDI After Pituitary Surgery Etiologic Characterization Conclusion References 6 Syndrome of Inappropriate Antidiuresis Epidemiology Pathophysiology Diagnosis and Differential Diagnosis Etiology Clinical Features Treatment Correction Rate Treatment Modalities Fluid Restriction Intravenous 3% Saline Vaptans Urea Furosemide and NaCl Demeclocycline SIAD Following Transsphenoidal Surgery Pathophysiology Epidemiology Isolated Hyponatremia Combined DI/Hyponatremia Predictive Factors for SIAD Clinical Features Diagnosis and Differential Diagnosis Treatment References 7 Hydro-saline Alterations in Central Adrenal Insufficiency Introduction Physiopathology Sodium and Water Balance: Physiology Notes and Main Hormonal Regulators Sodium and Water Balance Alterations in CAI Etiology and Epidemiology Chronic GC Administration Pituitary Tumors and Other Neoplastic Lesions of the Sellar Region Iatrogenic Hypophysitis: Immune Checkpoint Inhibitors Primary Autoimmune Hypophysitis Genetic Disorders Pituitary Apoplexy (Sheehan ́s Syndrome) Infiltrative Diseases of the Pituitary Region Infective Diseases of the Pituitary Region Empty Sella Subarachnoid Hemorrhage Traumatic Brain Injury Isolated ACTH Deficiency Laboratory Features and Clinical Picture Diagnosis Differential Diagnosis Treatment Prevention Conclusions References 8 Approach to Hyponatremia According to the Clinical Setting Introduction Etiopathogenesis of Hyponatremia Clinical Features of Hyponatremia Differential Diagnosis of Hyponatremia Treatment of Hyponatremia Hyponatremia in Oncology Hyponatremia in Neurology and Psychiatry Hyponatremia in Neurosurgery Hyponatremia in the Elderly Hyponatremia in Heart Failure Hyponatremia in Chronic Kidney Disease Hyponatremia in Liver Cirrhosis Hyponatremia in Emergency Medicine Hyponatremia and SARS-CoV-2 (COVID-19) Infection Conclusions Clinical Cases Case 1. Hyponatremia in Oncology - An Example of a Good Team Work Case 2. Hyponatremia in Emergency Medicine - An Example of a Mismanaged Case References 9 Electrolyte Disturbance in Congenital Adrenal Hyperplasia due to 21-OH Deficiency Introduction Electrolyte and Fluid Regulation in the Fetus and Neonate Water and Sodium Homeostasis During Fetal Life At Birth Renal Regulation of Water Excretion in the Neonate Renal Regulation of Sodium Excretion in the Neonate Mineralocorticoid Signaling Pathway Specificities of the Fetal and Neonatal Period Zona Glomerulosa, CYP21A2, and CYP11B2 Ontogenesis of Mineralocorticoid Receptor Physiological Role of Mineralocorticoid Signaling in the Fetus and Newborn Pathological Situations Congenital Adrenal Hyperplasia by 21 Hydroxylase Deficiency Pathophysiology Clinical Symptoms Hormonal Diagnosis Electrolyte Disturbances in CAH Treatment for Electrolyte Disturbances in CAH Patients Long-Term Cardiovascular and Metabolic Effects Emerging Therapeutics Conclusion References 10 Rare Forms of Congenital Adrenal Hyperplasia Affecting Electrolyte Homeostasis Introduction Lipoid Congenital Adrenal Hyperplasia (Star) Overview Epidemiology History and Molecular Genetics Physiology and Pathophysiology Clinical Presentation Laboratory Findings and Diagnosis Management and Therapeutics P450 Side-Chain Cleavage (P450SCC Deficiency) Overview Epidemiology History and Molecular Genetics Physiology and Pathophysiology Clinical Presentation Laboratory Findings and Diagnosis Management and Therapeutics 17-Alpha-Hydroxylase Deficiency Overview Epidemiology History and Molecular Genetics Physiology and Pathophysiology Clinical Presentation Laboratory Finding and Diagnosis Management and Therapeutics 3- β-Hydroxysteroid Dehydrogenase Type 2 Deficiency Overview Epidemiology History and Molecular Genetics Physiology and Pathophysiology Clinical Presentation Laboratory Finding and Diagnosis Management and Therapeutics 11-βeta-Hydroxylase Deficiency Overview Epidemiology History and Molecular Genetics Physiology and Pathophysiology Clinical Presentation Laboratory Finding and Diagnosis Management and Therapeutics Conclusion References 11 Apparent Mineralocorticoid Excess Introduction Mineralocorticoid-Dependent Hypertension Apparent Mineralocorticoid Excess Syndrome Etiology of AME Pathogenesis of AME Nonclassic Apparent Mineralocorticoid Excess Etiology of the Nonclassic AME Pathogenesis of NC-AME Genetics and Epigenetics Affecting HSD11B2 Gene: Role in NC-AME Epigenetics: DNA Methylation of HSD11B2 Gene Epigenetics: Non-Coding RNA Affecting HSD11B2 Gene Expression Exogenous Inhibitors of 11HSD2 Enzyme: Role in NC-AME Endogenous Inhibitors of 11βHSD2 Enzyme The Novel Combined Phenotype of NC-AME and Primary Aldosteronism Differential Diagnosis from AME and NC-AME Primary Aldosteronism Hypertensive Forms of Congenital Adrenal Hyperplasia (OMIM #202010 and #202110) Glucocorticoid Resistance (OMIM #138040) Liddle ́s Syndrome (OMIM #177200) Activating Mutation of Mineralocorticoid Receptor (OMIM #605115) Gordon Syndrome (OMIM #614495) Treatment for AME and NC-AME Conclusion References 12 Mineralocorticoid Resistance Introduction Aldosterone Biosynthesis Adrenal Cortex Steroidogenesis Aldosterone Biosynthesis Mechanism of Action of Aldosterone Aldosterone Action in Distal Nephron Mineralocorticoid Receptor Transcriptional Regulation by the MR ENaC Actions of Aldosterone in Epithelial Target Tissues: Genomic Effects Renal PHA1 Clinical Features MR Mutations Animal Models of Renal PHA1 Generalized PHA1 Clinical Findings ENaC Mutations Animal Models of ENaC Subunits Invalidation Secondary PHA1 Differential Diagnosis of PHA1 PHA1 Treatment Conclusions References 13 Primary Aldosteronism Introduction The Adrenal Gland Anatomy of the Adrenal Gland Vascularization and Innervation of the Adrenal Gland Renewal of the Adrenal Cortex Aldosterone Producing Cell Clusters (APCC) Regulation of Zona Glomerulosa Zonation Regulation of Zona Fasciculata Zonation Interaction Between Wnt/β-Catenin and ACTH/APMc Signaling Pathways Aldosterone Aldosterone Biosynthesis Action of Aldosterone Regulation of Aldosterone Biosynthesis Regulation by Angiotensin II Regulation by Potassium Regulation by ACTH Role of the β-Catenin in Regulating Mineralocorticoids Biosynthesis Regulation by Paracrine/Autocrine Factors Diagnostic and Treatment Outcome of Patients with Primary Aldosteronism Diagnosis of Primary Aldosteronism Treatment of Primary Aldosteronism Outcome of Patients with Unilateral Form of Primary Aldosteronism Etiology and Genetic of Primary Aldosteronism Sporadic Forms Mutations Affecting Cell Membrane Potential Mutations Affecting Directly Intracellular Calcium Concentration Familial Forms Familial Hyperaldosteronism Type I (FH-I) Familial Hyperaldosteronism Type II (FH-II) Familial Hyperaldosteronism Type III (FH-III) Familial Hyperaldosteronism Type IV (FH-IV) Primary Aldosteronism, Seizures, and Neurological Abnormalities (PASNA) Remodeling of Adrenal Glands with APA Zona Glomerulosa Hyperplasia Presence of Secondary Nodules Presence of APCC Presence of Possible APCC to APA Translational Lesions Prevalence of Somatic Mutations and Associated Correlations Prevalence of Somatic Mutations in APA and Genotype/Phenotype Correlations Mutations and Expression Profiles Correlations Mutations and Steroid Profiles Correlations Mutation and Targeted Treatment Risk Loci for Primary Aldosteronism Animal Models of Primary Aldosteronism Pathogenic Model for Primary Aldosteronism Development Conclusion: Toward a Precision Medicine in Primary Aldosteronism References 14 Mineralocorticoid Receptor and Aldosterone: From Hydro-saline Metabolism to Metabolic Diseases Introduction Aldosterone and Mineralocorticoid Receptor in the Regulation of Electrolytes and Water Homeostasis Renal Handling of Electrolytes and Water Regulation of Renal Ion Channels by the Aldosterone-Minealocorticoid Receptor Signaling Dysregulation of Renal Mineralocorticoid Receptor Signaling Pathways Regulation of Aldosterone Production Dysregulated Mineralocorticoid Receptor Signaling in the Kidney and Clinical Consequences Extra-Renal Mineralocorticoid Receptor Mineralocorticoid Receptor in the Vasculature Overactivation of Vascular Mineralocorticoid Receptor Mineralocorticoid Receptor in Cardiac Physiology Mineralocorticoid Receptor Overactivation in the Heart Role of Mineralocorticoid Receptor in Adipose Tissue Physiology Mineralocorticoid Receptor in Adipose Tissue Dysfunctions Mineralocorticoid Receptor Antagonists in Cardiovascular and Renal Dysfunctions Conclusion References 15 Hydrosaline Alterations in Cushing Disease Introduction Cushing ́s Syndrome: An Overview Pathophysiology Clinical Features of Cushing ́s Syndrome Diagnosis Etiological Diagnosis Treatment Water and Sodium Balance in Cushing ́s Disease Pathophysiology: The Role of Glucocorticoid and Mineralocorticoid Axis in Regulating Hydrosaline Metabolism Epidemiology Pathogenesis Diagnosis Treatment Potassium Balance in Cushing ́s Syndrome Epidemiology Pathophysiology Diagnosis Treatment Conclusions Clinical Case References Index