Sodium And Potassium Balance Lecture Highlights PDF

Sodium and Potassium Balance Lecture highlights 1. Renin-Angiotensin-Aldosterone system (RAAS), ADH vs Atrial Natriuretic Peptide (ANP) 2. Na+ balance and handling by the nephron 3. Mechanisms of RAAS actions 4. Clinical significance of angiotensin II antagonists 5. Aldosterone and related diseases...

Sodium and Potassium Balance Lecture highlights 1. Renin-Angiotensin-Aldosterone system (RAAS), ADH vs Atrial Natriuretic Peptide (ANP) 2. Na+ balance and handling by the nephron 3. Mechanisms of RAAS actions 4. Clinical significance of angiotensin II antagonists 5. Aldosterone and related diseases 6. Renal handling of potassium and its homeostasis, H+ and K+ ions 7. Hypo- and hyperkalemia Objectives: 1. Define the role of Na in maintaining extracellular fluid volume. 2. Identify the normal range of dietary Na + intake and major routes of Na + loss from the body. 3. Define terms hypovolemia, euvolemia, and hypervolemia; relate them to the concepts of sodium content and plasma sodium concentration. 4. Identify the tubular sites of Na + reabsorption and the effect of aldosterone. Discuss the function of ADH and the renin-angiotensin-aldosterone system (RAAS) in the regulation of extracellular fluid volume. 5. Identify factors that can promote renin release. 6. Describe the role of the RAAS in the regulation of systemic arterial blood pressure in volume-depleted states and in hypertension. 7. Explain the regulation of Na + balance by atrial natriuretic peptide (ANP). 8. Discuss the significance of aldosterone, its physiological effects and mechanisms that control its secretion; briefly describe the effects of abnormal aldosterone production. 9. Classify transport and permeability properties of the various nephron segments with regard to active and passive transport of NaCl, water and urea. Na+ & K+ Balance is Controlled by RAAS and ANP 1. Antidiuretic Hormone – ADH or arginine vasopressin Retains water Body Fluid Osmolarity ECF H2 O Na+ Retains Na+ Body Fluid Volume ADH and RAAS conserve body fluids 3. Atrial Natriuretic Peptide (ANP) increases H2O and Na+ excretion ANP stimulates decrease in ECF volume and osmolarity (excretion of Na+ and H2O) 2. Renin – angiotensinaldosterone System (RAAS) The balance of RAAS and ANP systems depends on changes in body fluid volume. In contrast, ADH release largely depends on plasma osmolarity. RAAS activation promotes Na+ reabsorption, helping ADH to retain water in the body. RAAS--ADH axis is opposed by ANP system. Reciprocal Roles: RAAS – ADH Axis versus ANP System Loss of Blood Volume Blood pressure Gain in Blood Volume RAAS and ADH Blood pressure ANP ANP Response of receptors sensitive to blood volume change in atria and other baroreceptors RAAS and ADH Cardiovascular system: cardiac output increase, vasoconstriction Behavior: Increased water intake Blood pressure is maintained or returns to normal Kidney: Water conservation to minimize its loss RAAS & ADH Response of receptors sensitive to blood volume change in atria and other baroreceptors ANP Cardiovascular system: cardiac output decrease, vasodilation Kidney: Increased Na+ and water excretion, decrease in ECF volume Blood pressure returns to normal Family of natriuretic peptides: ANP - Atrial natriuretic peptide (factor - ANF) BNP – Brain natriuretic peptide - misnomer, BNP is produced mainly in the cadiomyocytes CNP – C-type NP (endothelium, brain) Urodilatin (kidney) All natriuretic peptides: - have similar chemical structure - - derive from prohormones (propeptides) - bind to the same family of receptors (cyclic GMP increase) - have short half life in plasma (3- 20 minutes) due to degradation by vasopeptidases - are internalized via receptor – mediated endocytosis Only the role of ANP is established clearly in renal physiology Molecular structure of the natriuretic peptides. Plasma levels of B-type natriuretic peptide (BNP) have been shown to be predictive of outcome and to be clinically useful in diagnosis, management, and risk stratification of cardiovascular diseases such as heart failure and acute coronary syndromes ANP, Atrial natriuretic peptide; BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide. Vasoactive Molecules and the Kidney Gilbert, Richard E., Brenner and Rector's The Kidney, 11, 303-334.e13 Copyright © 2020 Copyright © 2020 by Elsevier, Inc. All rights reserved. Natriuretic peptides stimulate Na+ excretion in response to high blood volume and inhibit activity of RAAS Atrial natriuretic peptide (ANP) effects: - natriuresis - diuresis - smooth muscle cell relaxation GFR Medullary cardiovascular center Blood pressure reduction Increased blood volume stretches atria Release of Natriuretic peptides (ANP and others) Kidney Afferent arteriole dilation Adrenal cortex: Renin Aldosterone GFR Increase in Na+, Cl- and water excretion Hypothalamus ADH Sodium Balance: Na+ excretion daily equals its intake Na+ in diet 100-300 mEq/day Input Extracellular Fluid (ECF) Output Skin Losses GI Losses KIDNEY – 95% LOSSES Negative Na+ balance - Na+ excretion is greater than its intake When Na+ content of ECF is decreased = ↓ ECF volume or ECF volume contraction; blood volume and blood pressure drops. Positive Na+ balance - Na+ excretion is less than its intake When Na+ content of ECF is increased = ↑ ECF volume or ECF volume expansion; blood volume and blood pressure rises, and edema may develop. Which hormone directly promotes positive Na+ balance? a. ANP b. renin c. aldosterone Sodium restriction can aid in control of hypertension Sodium reabsorption in nephron ANG II! 70% 10% Na+ Na+K+2Cl- K+ 20% Proximal tubule – most of Na+ reabsorption, angiotensin II (ANG II) stimulates Na+/H+ antiport! ADH Na+ reabsorption in the thick ascending limb is stimulated by ADH Na+ reabsorption in the distal tubule and collecting duct is controlled by aldosterone via its effect on sodiumpotassium ATPases. What is the role of renin in RAAS? RAAS helps to restore low blood volume and pressure Initially ACE was discovered in the lung vasculature. It is also present in the endothelium of many other blood vessels. 1. Renin cleaves angiotensinogen yielding angiotensin I (inactive) ACE 2. Angiotensin I is converted into angiotensin II (active) by angiotensin-converting enzyme (ACE) 3. Angiotensin II binds to cell membrane receptors (AT1) and: a. constricts blood vessels b. stimulates release of ADH from the hypothalamus and aldosterone from the adrenal gland Angiotensinogen, a globulin released in blood from the liver, is the only substrate for renin Control of Body Fluid Osmolality and Volume Koeppen, Bruce M., MD, PhD, Berne and Levy Physiology, 35, 623-646 Copyright © 2018 Copyright © 2018 by Elsevier, Inc. All rights reserved. Does aldosterone change K+ balance? Aldosterone acts via mineralcorticoid receptor (MR). It was thought that MR distribution is limited to the kidney and sweat glands. However, MR was found in the heart, blood vessels and nervous system Pathophysiological role of RAAS In patients with congestive heart failure retention of Na+ caused by RAAS contributes to edema and development of the nephrotic syndrome. Comparison of Agents That Affect Aldosterone Action Tamargo, Juan, MD, PhD, Seminars in Nephrology, Volume 34, Issue 3, 285-306 Copyright © 2014 Elsevier Inc. Aldosterone promotes salt retention in the distal nephron and helps to maintain blood volume and pressure RAAS promotes positive sodium balance and plays an important role in physiological adaptation Blood pressure rises Salt retention Adrenal Gland Aldosterone Angiotensin II Angiotensinconverting enzyme Renal artery and vein Angiotensin I Renin Angiotensinogen Blood pressure falls Secretion of renin from the granular cells of the juxtaglomerular apparatus is the ratelimiting step in RAAS activation. Juxtaglomerular Apparatus (JGA): 1. granular cells, arterioles 2. macula densa, specialized cells of the renal tubule 3. external mesangial cells Functions of the cells of JGA: Granular cells - renin release! Macula - sensing flow What aredensa the stimuli for renin of filtrate. release? ANATOMY OF THE URINARY TRACT ${parentCitation.authFull}, Netter Collection of Medical Illustrations: Urinary System, The, SECTION 1, 1-28 Copyright © 2012 Copyright © 2012 by Saunders, an imprint of Elsevier Inc. Renin secretion is stimulated by a decreased pressure in the afferent arterioles! Renin release is increased by: 1. low perfusion pressure (afferent arteriole) 2. low tubular flow (macula densa) 3. high sympathetic nervous activity Renin secretion can be elevated even when systemic blood pressure is normal or high; for example in patients with renal artery stenosis (narrowing). Low blood flow and pressure in the afferent arterioles plays a crucial role. Regulation of Extracellular Fluid Volume and Osmolarity Mulroney, Susan E., PhD, Netter's Essential Physiology, Chapter 20, 231-236 Copyright © 2016 Copyright © 2016 by Elsevier, Inc. All rights reserved. A decrease in blood pressure due to hemorrhage (volume contraction) is a typical stimulus for RAAS activation Kidney Secretion of renin from the granular cells of the juxtaglomerular apparatus is the rate-limiting step in angiotensin II formation. ? Water retention Control of Body Fluid Osmolality and Volume Koeppen, Bruce M., MD, PhD, Berne and Levy Physiology, 35, 623-646 Copyright © 2018 Copyright © 2018 by Elsevier, Inc. All rights reserved. ? Na+ retention Angiotensin II stimulates: 1. aldosterone secretion from the adrenal gland and 2. ADH release from the hypothalamus. What are other actions of angiotensin II? ANG II effects Angiotensin II, an octapeptide, acts on angiotensin receptor (AT1) inducing a spectrum of effects including strong vasoconstriction and increasing heart rate. In addition, ANG II stimulates NaCl tubular reabsorption largely in the proximal tubule (PCT). These ANG II actions result in elevation of blood pressure. Atherosclerosis Risk Factors : Familial Arteriosclerosis Liu, Zhao-Jun, Rutherford's Vascular Surgery and Endovascular Therapy, Chapter 15, 164-173.e4 Copyright © 2019 Copyright © 2019 by Elsevier, Inc. All rights reserved. AT1R Deciphering the Identity of Renin Cells in Health and Disease Guessoum, Omar, Trends in Molecular Medicine, Volume 27, Issue 3, 280-292 Copyright © 2020 Elsevier Ltd Low pressure Angiotensinogen, a 485-amino-acid long peptide is cleaved into angiotensin I, an inactive decapeptide. February, 1945 Blood pressure of Roosevelt? Varied between 180/110 and 260/150 mm Hg Did they prescribe antihypertensive medication for Roosevelt? In the late 1940s, Dr. Charles Friedberg wrote in his textbook Diseases of the Heart: “ In a patient with mild benign hypertension defined as blood pressure <200/<100 mm Hg, there is no indication for use of hypotensive drugs” Phenobarbital (barbiturate) and massages Roosevelt’s maximal blood pressure? >300/190 mm Hg. Death from hemorrhagic stroke. Hypertension is the most important modifiable risk factor for stroke Current estimates Years Stroke as most common cause of death in USA are that 77% of Until 1959 The second those who have a 1959-2007 The third first stroke have had a blood pressure 2008-2012 The fourth (BP) above 2013-2014 The fifth 140/90 mm Hg. Venoms of Latin American pit vipers induce drastic hypotension! Why? Captopril = the first ACE inhibitor, a peptide with active sequence found in the venom of brazilian vipers Use of home monitoring of blood pressure to evaluate the effectiveness of an antihypertensive drug (enalapril). Note the rapidity of the response. (Modified from Chatellier G, Day M, Bobrie G, Ménard J. Feasibility study of N-of-1 trials with blood pressure self-monitoring in hypertension. Hypertension . 1995;25:294-301.) Home Monitoring of Blood Pressure Campbell, Patrick T., Hypertension: A Companion to Braunwald’s Heart Disease, Chapter 5, 45-56 Copyright © 2013 Copyright © 2013, 2007 by Saunders, an imprint of Elsevier Inc. Antihypertensive drugs – ACE inhibitors and angiotensin receptor blockers (ARB’s) (or antagonists ) renin angiotensinogen angiotensin I ACE inhibitors ACE (captopril, enalapril, trandolapril, etc.) AT1 receptor blockers (losartan, angiotensin II AT 1 receptors valsartan, etc.) Aldosterone Na+ & H2O retention Dilation - peripheral resistance Blood volume & cardiac output Blood pressure Agonists = compounds that bind receptors (ligands) and produce typical physiological response Antagonists = compounds that bind to receptors and inhibit physiological response What else should we know about ACE Inhibitors? Side effect of ACE inhibitors – coughing due to an increase in bradykinin, an inflammatory mediator. Normal Blood Pressure Control and the Evaluation of Hypertension Lawton, William J., Comprehensive Clinical Nephrology, Chapter 33, 392-406 Copyright © 2015 Copyright © 2015, 2010, 2007, 2003, 2000 by Saunders, an imprint of Elsevier Inc AT1 mediates most of the known Angiotensin II effects Vasodilation, inflammation of airways Degraded fragment Physiological role of AT2 is under investigation To avoid bradykinin-induced coughing effect which of the following antihypertensive drugs can be used? a. Losartan b. Valsartan c. Candesartan d. All of the above Interactions and functions of renin-angiotensin and kallikrein-kinin systems, substances that play a role in blood pressure control, coagulation and inflammation. Bradykinin is a part of this system. ACE, Angiotensin-converting enzyme; ANG II, angiotensin II; AT1 , AT2 , angiotensin receptors; SNSA, sympathetic nervous system activity; UNa V, urinary sodium excretion; Endothelins, a group of powerful vasoconstrictor peptides. If neither ACE inhibitors nor ARBs are tolerated, what is another option to decrease blood pressure in patients affecting the RAAS? Blockade of β1-receptors in the kidney ↓ sympathetically stimulated renin secretion, ↓ forma on of angiotensin II and the subsequent release of aldosterone β-blockers (e.g. metoprolol) lower blood pressure acting at several sites: 1. cardiac β1-receptor blockade &↓ heart rate and contrac lity → ↓cardiac output 2. renal β1-receptor blockade & ↓ renin release Location of renal β1-receptors? What is aliskiren? Antihypertensive Drugs Stevens, Craig W., PhD, Brenner and Stevens’ Pharmacology, CHAPTER 10, 105-117, Copyright © 2023 Copyright © 2023 by Elsevier, Inc. All rights reserved. Aliskiren = Direct Renin Inhibitor Activation Aliskiren is the first orally effective direct renin inhibitor approved for treatment of hypertension. It binds to the active site of renin, preventing cleavage of angiotensinogen and formation of angiotensin I. Thus, aliskiren lowers plasma renin activity and levels of angiotensin I and II. Aliskiren is rarely used. Oral Direct Renin Inhibition: Premise, Promise, and Potential Limitations of a New Antihypertensive Drug Shafiq, Moiz M., MD, American Journal of Medicine, The, Volume 121, Issue 4, 265-271 Copyright © 2008 Elsevier Inc . Aldosterone controls Na+ and K+ plasma level and maintains ECF volume Steroid hormone, mineralcorticoid secreted from the zona glomerulosa of the adrenal cortex Major stimuli for release: a. high plasma angiotensin II b. high plasma K+ Minor stimuli: acidosis hyponatremia ACTH Amiloride - sensitive epithelial sodium channels (ENaC) Distal nephronPrincipal cell Interstitium Na+ Na+ K+ Lumen Physiological action - increase in: a. Na+ reabsorption b. K+ secretion c. H+ secretion ATP K+ ${parentCitation.authFull}, Netter Collection of Medical Illustrations - Endocrine System, The, SECTION 3, 65-65 Copyright © 2011 Copyright © 2011 by Saunders, an imprint of Elsevier Inc. Histology of adrenal gland Aldo Cortisol Principal cell of distal nephron Aldosterone, a Cytoplasmic MR lipophilic steroid, diffuses across the Lumen cell membrane and Na+ Na+ binds to Nucleus cytoplasmic ATP mineralcorticoid receptor (MR). + This newly formed + K K complex triggers transcription in the nucleus. Cytoplasmic MR Additional Na+ H+ channels and Na/K ATP pumps are made. The overall effect – an increase in Na+ reabsorption and K+ secretion Nucleus H+ Interstitium ATP K+ Alpha - intercalated cell Peritubular capillary Aldosterone Aldosterone promotes Na+ reabsorption (retention) and K+ secretion (loss) Distal nephronPrincipal cell Amiloride sensitive sodium channel Na+ Na+ ATP K+ K+ Interstitium Lumen Aldosterone deficit promotes Na+ (water) loss and K+ retention Aldosterone and Diseases Hypersecretion: Primary hyperaldosteronism (Conn’s syndrome) – renin-independent aldosterone overproduction (mostly benign adrenal gland tumors), aldosterone , renin 1. Increased Na+ retention and associated water retention promote increased ECF volume – hypervolemia, systemic hypertension and hypernatremia 2. Increased K+ secretion promotes hypokalemia, which may be associated with metabolic alkalosis (low plasma H+ due to its excessive secretion) Patients with hyperaldosteronism can be asymptomatic! With no or mild elevation of blood pressure or only hypokalemia! Primary aldosteronism Orrego, John J., Endocrine Secrets, CHAPTER 32, 257-264.e1 Copyright © 2020 Copyright © 2020 by Elsevier, Inc. All rights reserved. “Aldosterone escape” Increased ECF volume promotes activation of ANP system, which can cause polyuria and reduction in hypernatremia (“aldosterone escape”) Stenotic kidney responds to reduced perfusion with activation of renin-angiotensin system, producing widespread effects that include rise in arterial pressure. Elevated pressures subject the nonstenotic kidney to elevated pressure natriuresis that diminishes (or even overrides) hypertension and hypernatremia induced by the stenotic kidney (“aldosterone escape”). Pathophysiology of Renal Artery Disease Textor, Stephen C., Vascular Medicine: A Companion to Braunwald's Heart Disease, Chapter 22, 285-295 Copyright © 2013 Copyright © 2013, 2006 by Saunders, an imprint of Elsevier Inc. Hypernatremia does not necessarily means positive sodium balance! Different Types of Hypernatremia: 1. With low total body sodium and water: heat stroke (sweat is hyposmotic fluid!) 2. With normal sodium and low total body water: diabetes insipidus 3. With increased total body sodium: Conn’s syndrome Primary hyperaldosteronism (Conn’s syndrome) = adrenal cortical tumor Plasma renin activity Aldosterone Cardiovascular damage in hyperaldosteronism was thought to be mainly a consequence of elevated blood pressure. Recent studies suggest direct deleterious effect of aldosterone on the heart and blood vessels. ADRENAL ${parentCitation.authFull}, Netter Collection of Medical Illustrations - Endocrine System, The, SECTION 3, 65-65 Copyright © 2011 Copyright © 2011 by Saunders, an imprint of Elsevier Inc. Secondary hyperaldosteronism – renin-dependent or renovascular hypertension Classical example – renal artery stenosis, renin aldosterone Cardiovascular damage in hyperaldosteronism was thought to be mainly a consequence of elevated blood pressure. Recent studies suggest direct deleterious effect of aldosterone on the heart and blood vessels. ADRENAL ${parentCitation.authFull}, Netter Collection of Medical Illustrations – Endocrine System, The, SECTION 3, 65-65 Copyright © 2011 Copyright © 2011 by Saunders, an imprint of Elsevier Inc. Hypertension in bilateral renal artery stenosis. Advanced atherosclerosis ( From Safian RD, Textor SC. Renal-artery stenosis. N Engl J Med 2001;344(6):431–42; with permission. Copyright © 2001, Massachusetts Medical Society.) Management of Heart Failure with Renal Artery Ischemia Rao, Madhav V., MD, Cardiology Clinics, Volume 29, Issue 3, 433-445 Copyright © 2011 Elsevier Inc. Decreased plasma flow in the renal arteries induces high renin and aldosterone secretion despite high blood pressure Decreased renal plasma flow and prerenal azotemia Prerenal Azotemia Diagnosis: FENa BUN/Cr Intrarenal Azotemia Diagnosis: urinalysis, biopsy Postrenal Azotemia Diagnosis: Ultrasound Vascular volume depletion Glomerular due to gastrointestinal, renal (Glomerulonephritis) and other fluid loss Prostatic disease Shock due to sepsis, cardiac failure Tubulo-Interstitial (acute tubular necrosis or interstitial nephritis) Ureteral obstruction Bilateral Renal Artery Stenosis Vascular (vasculitis) Obstruction due to malignancy *55 year-old patient, 99% stenosis right renal artery, ~60% stenosis left renal artery, BP 185/120 mm Hg. FENa What is FENa? Prerenal azotemia is associated with RAAS activation, high aldosterone and increased reabsorption of Na+! Prerenal Acute Kidney Injury Prerenal azotemia is associated with RAAS activation, high aldosterone and increased reabsorption of Na+! What is FENa? Regulation of Extracellular Fluid Volume and Osmolarity Mulroney, Susan E., PhD, Netter's Essential Physiology, Chapter 20, 231-236 Copyright © 2016 Copyright © 2016 by Elsevier, Inc. All rights reserved. Fractional excretion of sodium: FENa = Amount of excreted Na+ x 100% Amount of filtered Na+ Ratio The practical formula for FENa: FENa = UNa x PCr x 100% PNa x UCr UNa and PNa – Na+ concentration of urine and plasma, PCr x UCr – plasma & urine creatinine FENa helps to differentiate prerenal azotemia from other causes of acute kidney injury in patients with oliguria In prerenal azotemia, FENa is low < than 1 % Na+ loss is low because of elevated Na+ reabsorption & Its retention triggered by RAAS activation. Since many drugs, for instance, diuretics, affect Na+ and creatinine, FENA is not always reliable, especially in young children and elderly. FENa is > than 1 % in acute tubular necrosis (intrarenal azotemia) Tubular necrosis = low Na+ reabsorption = high excretion of Na+ in urine Causes of Acute Renal Azotemia Prerenal (1-2) Postrenal (8) Systemic Complications : Renal Myers, Daniel J., Rutherford's Vascular Surgery and Endovascular Therapy, Chapter 44, 555-566.e4 GBM , Glomerular basement membrane; IgA , immunoglobulin A. (Adapted from Ashley J, et al. Pathophysiology and etiology of acute kidney in... Copyright © 2019 Copyright © 2019 by Elsevier, Inc. All rights reserved. Intrarenal Azotemia (3-7) ! Postrenal azotemia Reduction in GFR and BUN elevation may also be caused by other pathophysiological mechanisms, for example, by urine flow obstruction due to kidney stones (“no way out”). In this case, elevation in BUN indicates postrenal azotemia (the cause is “after” kidney). Various Causes of Hyperaldosteronism Disorder Aldosterone Renin Plasma K+ Primary hyperaldosteronism Renin secreting tumor Renovascular hypertension -N -N -N Diuretics Bartter’s syndrome -N = normal value What is Bartter’s syndrome? Source: Evaluation of Endocrine Function by H. A. Guberand A. F. Farag In: Henry's Clinical Diagnosis and Management by Laboratory Methods. 2017, Chapter 24, 362-399.e5 -N -N Bartter syndrome, mutations of genes coding for Na/K/2Cl transporter: symptoms similar to those which can be evoked by the abuse of loop diuretics, i.e. hypokalemia, hypercalceuria, excessive loss of fluid (polyuria) Loop diuretics decrease positive lumen charge & paracellular transport of Ca++ and Mg++ Hyposecretion of aldosterone – hypoaldosteronism, (isolated, not associate with decreased secretion of other hormones from the adrenal cortex) 1. Increased Na+ loss (excretion) and associated water loss are likely to cause decreased ECF volume - hypovolemia, hypotension and hyponatremia 2. Decreased potassium secretion causes hyperkalemia (high plasma K+) 3. Decreased hydrogen ion secretion may cause metabolic acidosis Removal of the adrenal glands leads to death within a few days! Medications: hydrocortisone daily; *fludrocortisone daily; prednisone twice daily; methyltestosterone daily; liothyronine twice daily; vitamin C twice daily; atropine sulfate, as needed. * mineralcorticoid for their work with the hormones of the adrenal gland Optimal glucocorticoid replacement in adrenal insufficiency Øksnes, Marianne, MD, PhD, Best Practice & Research: Clinical Endocrinology & Metabolism, Volume 29, Issue 1, 3-15 Copyright © 2014 Elsevier Ltd Addison’s disease or primary adrenal cortical hyposecretion Both low cortisol (zona fasciculata) and low aldosterone (zona glomerulosa) "John F. Kennedy, White House color photo portrait" by Cecil Stoughton, White House - This media is available in the holdings of the National Archives and Records Administration, cataloged under the ARC Identifier (National Archives Identifier) 194255.This tag does not indicate the copyright status of the attached work. Licensed under Public Domain via Commons https://commons.wikimedia.org/wiki/File:John_F._Kennedy,_White_House_color_photo_portrait.jpg#/media/File:John_F._Kennedy,_White_House_color_photo_portrait.jpg • Loss of weight, dehydration • Low blood pressure, hypovolemia, postural hypotension • Abnormal oral and cutaneous pigmentation • Gastrointestinal disturbances • Anorexia, weakness, hypoglycemia & fatigue Patients without adequate replacement therapy die in coma. ${parentCitation.authFull}, Netter Collection of Medical Illustrations - Endocrine System, The, SECTION 3, 65-65 Copyright © 2011 Copyright © 2011 by Saunders, an imprint of Elsevier Inc. Primary hypoadrenalism (Addison's disease): symptoms and signs. Bold italic type indicates signs of greater discriminant value. Endocrine disease Levy, Miles J, Kumar and Clark's Clinical Medicine, 26, 1175-1240 Copyright © 2017 © 2017 Elsevier Ltd. All rights reserved. The hyperpigmentation (shown in contrast to the physician's hand) is accentuated in sun-exposed skin and can also involve sites of trauma, skin creases and mucosae. Dermatologic Manifestations in Patients with Systemic Disease Schwarzenberger, Kathryn, Dermatology, 53, 761-781 Copyright © 2012 © 2012, Elsevier Limited. All rights reserved. Causes of primary hypoaldosteronism Addison's disease = damaged adrenal glands: - autoimmune - infections - cancer Chronic adrenal cortical insufficiency , Addison disease , is a clinical syndrome characterized by progressive weakness and fatigue, hypotension, weight loss, skin and mucosal hyperpigmentation, and abdominal problems. Laboratory test results show hyperkalemia, hyponatremia and volume depletion (decrease in mineralocorticoids such as aldosterone). . Isolated hypoaldosteronism: - Hyporeninism – atrophy of juxtaglomerular apparatus, - an inherited disorder of aldosterone biosynthesis, - removal of aldosterone-secreting adenomas Endocrine System Buja, L. Maximilian, MD, Netter's Illustrated Human Pathology, Chapter 12, 411-440 Copyright © 2014 Copyright © 2014, 2005 by Saunders, an imprint of Elsevier Inc. Various Causes of Hypoaldosteronism Disorder Aldosterone Renin Serum K + Addison's disease ↓ ↑ ↑ Isolated primary hypoaldosteronism ↓ ↑ ↑ Hyporeninimic hypoaldosteronism ↓ ↓ ↑ Liddle's syndrome ↓ ↓ ↓? (hereditary problems with aldosterone synthesis) (atrophy of the juxtaglomerular apparatus) What is Liddle’s syndrome? Source: Evaluation of Endocrine Function by H. A. Guberand A. F. Farag In: Henry's Clinical Diagnosis and Management by Laboratory Methods. 2017, Chapter 24, 362-399.e5 Liddle syndrome (pseudohyperaldosteronism, hypertension and low aldo.) Hereditary problem: Amiloride sensitive epithelial sodium channels (ENAC) are Na+ defective (“hyperactive”) = Na+ excessive K+ loss + Na with urine. Na+? K+ Principal cell Na+ ATP K+ Blood K+ ? Urine Major stimuli for aldosterone release: a. high plasma angiotensin II b. high plasma K+ Low potassium = absence of stimuli for aldosterone secretion, Various Causes of Hypoaldosteronism Disorder Aldosterone Renin Serum K + Addison's disease ↓ ↑ ↑ Isolated primary hypoaldosteronism ↓ ↑ ↑ Hyporeninimic hypoaldosteronism ↓ ↓ ↑ Liddle's syndrome ↓ ↓ ↓ What is Liddle’s syndrome? Liddle's syndrome constitutes an autosomal dominant gain in function of the amiloride-sensitive Na+ channel (ENAC) of the distal tubule and collective duct. Patients manifest severe hypertension with hypokalemia, unresponsive to spironolactone yet sensitive to amiloride. Source: Evaluation of Endocrine Function by H. A. Guberand A. F. Farag In: Henry's Clinical Diagnosis and Management by Laboratory Methods. 2017, Chapter 24, 362-399.e5