ace |IMKSAP & Medical Knowledge Self-Assessment Program Endocrinology and Metabolism SACP Leong tema Medi, Improving vorAttention MKSAP 18 Complete subscribers: I you are receiving the MKSAP 18 print books as part of your MAS Complete subscription, remiember that you will receive Updates In your online account through MKSAP 18 Digital's New Updates. New Info Updates will focus on practice changing updates. includ ing new guidelines. You will also receive four sets of MKSAP 18 Extension (Questions (formerly MKSAP Update Questions) that will allow you t eam, ME credits and MOC points through January 2024, Not a MKSAP 18 Complete subscriber? I-you wish to add MKSAP 18 Digital to your print subscription at any time. upgrade to MKSAP 18 Complete for the mest value packed, cost efficient combination of MKSAP products. Pleasecall our ACP Member and Customer Service Department, znd they will help vou areange easy access ta MKSAP iS Complete, As partof MKSAP 18 Complete, you will receive MESAPI8 Digital, Including regutar concent updates through New info Updates, and fourscts ‘07 NKSAPISEntension Questions formeriy MKSAP Update Questions) that willallow you to earn CME eredits and MOC points through 2 receive MKSAP 18 Flashcards, Virtual Dx, and Board bask (print and e-book) at no extra charge. 24. You will ACP Member and Customer Service ‘Outside the U.S, call 215-351-2600 (Monday to Friday, 9 am S pm ET) Disclaimer Regarding Direct Purchases from Online Retailers “ME and/or MOC for MKSAP 18 is available only if you purchase the pro- gram directly from ACP, CME eredits and MOC points cannot be awarded to hose purchasers who have purchased the program from non authorized sellets, such as Amazon, eBay, orany other such uniline retailerace |MIKSAP & Endocrinology and MetabolismWelcome tothe Endocrinology and Metabolism Section of MKSAP 18! In these pages, you will find update information on disorders f'ghuense metabolism, disorders of the pitettary gland, disonters of the adrenal glands, disorders of the thyroid gland, reproduction disorders, transgender hormone therapy ‘management, and calcium and bone disorders. All ofthese topics are uniquely focused on the needs of generalistsand shcpecialisss outside of endocrinology: The core content of MKSAP 18 has been developed 2s in previous editions all essential information that is newly researched. and written in TI topie areas ofintemal medicine-created by dozens of leading. generalists and subspecialists and guid by certification and recertification requirements, emerging knowledge in the feld, and user feecback. MKSAP 18 also coniains 1200 all new peer-reviewed, psychometrically validated, multiple choice questions (MCQs) for self-assessment and study, inclucling 84 in Frdoerinology ancl Metabolism, MKSAP 18 continues to inchude High Vaiue Care (HVC) recommendations, based on the concept of balancing clinical benefit with costs and harms, with associated MCQs illustrating these princi ples and IIVC Key Points called out in the text. internists practicing in the hospital setting can easily find comprehensive Hspitalist focused content and MCQs, specially designated in blue and with the (0 symbol IF you purchased MKSAP 18 Complete, you also have access to MKSAP 18 Digital, with additional tools allowing you to customize your learning experience. MKSAP Digital includes regular text updates with new, practice-charging informa: tion, 200 new self assessment questions, and enhanced custom-quiz options. MKSAP Complete also includes more than 1200 electronic, adapiive learning-ennanced flashcards for quick review of important concepts. a8 well as an updated and enhanced version of Virtual Dx. MKSAP's image-based sell-assessment tool. Asbefore. MKSAP 18 Digitalis optimized for use ‘on your mobile devices, with iOS. and Android based apps allowing you to syne between your appsand online account and submit for CME credits and MOC points online, Pleace visit usat the MKSAP Resource Site (mlssap.aeponline.o7g) to find oat how we ean help you study, earn CME eredit and MOC points, and stay up to date On behalf of the many internists who have offered their time and expertise to ereate the conten! for MKSAP 18 and the edito ral staff who work to bring this material to you 1n the best possible way, we are honored that you have chosen to use MKSAP 18and appreciate any feedback about the program you may have. Pease feel free fo send any comments io mksap_editorsa aeponline.org, Sincerely, JSnictes Patrick C. Alguire, MD, FACP Editor in Chief Senior Viee President Emeritus Medical Fducation Division American College of PhysiciansEndocrinology and Metabolism Committee Cynthia A. Burns, MD, FACR Section Editor! Director of Undergraduate Medical Education in Internal Medicine {internal Medicine Clerkship Director and Subspecialty Acting Internships Course Director Associate Professor of Internal Medicine Section of Frelocrinalogy and Metabolism ‘Wake Forest School of Medicine ‘Winston-Salem, North Carolina Leigh M. Eek, MD, FACP Program’ bireetor, Internal Medicine Residency Program Associate Professor of Medicine ‘University of Kansas Health System Sansas City, Kansas ‘Kurt A. Kennel, MD? Assistant Professor of Medicine Dinision of Endocrinology, Metabolism and Nutrition Mayo Clinic College of Medicine and Science Rochester, Minneoia, ‘Wanda C. Lakey, MD, MHS, FACP* Associate Professor of Medicine Disision of Endocrinology Duke Unversity Medical Center Durham VA Medical Center ‘Durham, North Camoline ‘Sarah E. Mayson, MD* Assistant Professor Division of Endoerinology, Metabolism and Diabetes Canersity of Colorado School of Medicine Aaron. Colorado Farah Morgan, MD! Assistant Professor Cooper Medical School of Rowan University Endocrine Fellowship Program Director Cooper University Hospital Camden, New Jersey Neen Natt, MD! Associate Professor, Endocrinology Mayo Clinic College of Medicine and Science Rochester, Minnesota Editor-in-Chief Patrick C. Alguire, MD, PACP? Senior Vice President Emeritus, Medical Education American College of Physicians Philadelphia, Pennsylvania Deputy Editor Denise M. Dupras, MD, PhD, FACP! Associate Program Director Department of ternal Medicine Associate Professor of Medicine Mayo Clinic Collegeof Medicine ard Science Rochester, bliancsota Endocrinology and Metabolism Reviewers Karen Barnard, MBBCH! Shakar S etfaanall, I ACE Michelle |. Cordaka Kise. MD! Benjamin A. Dennis, MD! uban Dhaliwal. ND! Antonette Brigih Frasch, MD. FAG? Peter A. Golden, MD? Dona Leste Gray, FACE Aran Sathananthan, MD. FACE Sarah I See, MD, FACP! Michael, Shanik: MD. ACD Hospital Medicine Endocrinology and Metabolism Reviewers Kyaw K. Soe, MD, FACP Scott M. Stevens, MD, FACP! Endocrinology and Metabolism ACP Editorial Staff Randy Hendrickson’, Production Administrator/Eiitor Julia Nawrocki! Digital Content Associate /Faitor Margaret Wells, Director, Self Assessment and Faveational Programs Becky Krumm, Managing Editor, Self-Assessment ancl Educational ProgramsACP Principal Staff Davoren Chick, MD, FACE Senior Vice President, Medical Education Patriek C. Alguire, MD, FACP* Senior Vice President Emeritus, Medical Réueation Sean McKinney! Vice President, Medical Education Margaret Wells Direcior, Self Assessment and Educational Programs Becky Krumm' Managing Fitor Nalerie Dangovetsky! administraor Ellen MeDorald, PRD" Senior Staff Editor ‘Megan Zhorowski? Senior Staff Faltor Jackie Twomey! Senior Staff Eater Randy Hendrickson! Production Administrator’ Editor Julia Nawrocki! Digital Content Associate/taitor Linnea Donnarummat! Staff Ealtor Chuck Emig! Staff Ealtor Joysa Winter! Staff Editor Kimberly Kerns! Administrative Qoordinator gua cn gs sevcoecomunedupr eden poset Disclosure of Relationships with any entity producing, marketing, reselling, or Patrick C. Alguire, MD, FACP Royalties Upfobate Davoren Chick, MD, FACP Royalties Wolters Kluwer Publishing Consultariship EBSCO Health's DynaMed Plus Other (Ovener and sole proprietor of Coding 101, 11; Spouse: research consultant for Vedanta Biosciences Leigh M. Bek, MD, FACE. Consultantship NowoNordisk Antonette Brigid! Frasch, MD, FACE Consultantsinip Meslical Reviewers of America Peier A. Goulden, MD Research Grants/Conireets NovoNordisk Dona Leslie Gray, MD, FACP- Speakers Bureau Janssen, Sanofi Kurt A. Kennel, MD Consultantsiip Acupers Honoraria ACGME J, American Association of Clinical Endocrinology Wanda C. Lakey, MD, MHS, FACP Research Grants/ Contracts Janssen, Regeneron, Amarin, Sanofi/Aventis Sarah E. Mayson, MD. ther: Principal Investigator, Rosetta Genomes Airani Sathananthan, MD, FACP Research Grante/Contracts Principal investigator for Western University for NowoNardisk/Sanofi Michael H. Shanik MD, FACP. Research Grants/Contracts NovoNordisk, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Amarin Speakers Bureau: NovoNordisk, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Amarin Consultantship NovoNordisk, Boehringer Ingelheim, EU Lilly Amann Scott M. Stevens, MD. PACP Research Grants/Contracts Bristol-Myers SquibbAcknowledgments ‘The American Cottage of Fhystetans (ACP) gratefully acknowledges the special contributions to the develop- ment and produetion ofthe 18th edition ofthe Medical Knowledge Sel assessment Program’ (MKSAP* 18) made by the following people: Graphic Design: Barry Moshinski (Director, Graphic Services) Michael Ripea (Graphics Technical Adnuntstator, and Jenner Gropper(Graphle Designer. Production/Systems: Dan Holfinann (Director, information Technology), Scott Hu (Manager, Cunient Sysiems). Nei! Kohl ‘Senior Architect), and Cheis Patterson Genior Architect) MSAD 18 Digitale Under the direction of Steven Spadt (Senior Vice President, Teclmoiogy), the digital version of MKSAP 18 was developed within the ACP’s Digital Products and Services Department, led by Brian Sweigant (Director. Digital Products and Services). Other membersof the team included Dan Barron (Senior Web Application Developer Architect), Chris Forrest (Senior Software Developer Design Lead), Kathleen Hoover (Senor Web Developer), Kara Regis (Manager, User Interface Design and Development), Braid Lord (Senfor Web Application Developer). and Join MeKnight (Senior Web Developer). The College also wishes to acknowledge that many other Persons, too numerous lo mention, have contributed to the production of this program. Without their dedicated efforts, ‘this program woald not have been possible. MKSAP Resource Site (mksap.acponline.org) The HKSAP Resource Site (noap acponline or) com tinually updated site that provides links to MKSAP 18 online answer sheets for print subseribers; arcess to NKSAP 1 Digital; Board Basics” «-book acess instructions informa ‘ion on Continuing Medical Education (CME), Maintenance of Certification (MOO). and interatonal Continuing Professional Development (CPD) andl MOC, erat and other new information, International MOC/CPD For information and instructions on submission of inter nationst MOCICPD, please gp to the NKSAP Resource Site lmksapacponline.ory) Continuing Medical Education The American College of Physicians is accredited by the Acereditation Council for Continuing Medical Education (ACCME) to provide continuing medi physicians. The American Collegeof Physicians designates this enduring ‘material, MKSAP 18 fors maximum of 275 AMA PRA Category 1LGredits!, Physiciansshould claim only the credit commenst sate withthe extent oftheir participation in theactvity, Up to 19 AMA PRA Gategory 1 Credits™are available from Decemiver 31, 2018, to December 31, 2021, for the MKSAP 18, Endocrinology and Metabolism section. Learning Objectives The learning objectives of MKSAP 18 are Lo + Close gaps between actual care in your practice and pre ‘ered standards ofeare, hase on best evidence «+ Diagnose atseuse states (hat are less common and some times overlooked and confusing Improve management of comorbid conditions that ean complicate patent care Determine when to refer patients for surgery or care by subspecialets Pas he ABIM Cerlfiation Fxaratnatton Pas che ABIM Maintenance of Certification Examination Target Audience ‘© General internists and primary care physicians ‘+ Subspecialists who need to remain up to date in internal medicine «» Residents preparing for the certifving examination in intemal medicine + Plysiclans preparing for maintenance of certiieation tn, internal medicine [recertification) ABIM Maintenance of Certificat Check the MRSAP Resource Site (mksap_acponline.org) for the Latest information cn haw MKSAP tows ean be used to apply @ the American Board of Internal Medicine (ABIN) for Maintenance of Certification (MOC) points following ‘completion of the CME activity Successful completion of the CME activity, which ineludes participation in the evaluation component, enables the participant to 2am up to 275 mecical knowledge MUC points in the ABIM's MOC program: I! isthe CMEactivity provider's responsibility to submnit participant completion information to ACCME for the purpose of granting MOC credit, Earn Instantaneous CME Credits or MOC Points Online Print sabseribers can enter thelr arswers online to eam instantaneous CME credits or MOC points. You can submit your answers using online answer sheets that are provided at mksap acponline org, where a record of your NKSAP 18 sill be available, To carn CME credits orto apply forMOC points, you need to answer all of the questions ina tes. and carn a score of al lest 50% correct (number of correct answers divided hy the total number of questions). Please rote that ifyoware applying for MOC points, you must also center your birth date and ABIM candidate number, Take either of the following approaches: 1. Use the printed answer sheet at the back of this book to record your answers. Go to mksap.zepomline.o7g, access the appropriate online answer sheet, transcribe your answers, and sabmil your test for instantaneous CME ‘redhits oF MOC points, There Is no additional fee for this service, Goto mksapacponline.org, aceess the appropriate anline anawer sheet, direclly enter your answers, and submit {our fest br Instantaneous CME credits or MOC potnts, ‘There isno additional fee or this service, Earn CME Credits or MOC Points by Mail or Fax Pay «$20 processing fee per answer sheet and submit the printed answer sheet atthe back of this book by mail or fax, as instructed on the answer sheet. Make sure you cal culate your score and enter your birth date and ABIM ean: ‘digate number, and fax the answer sheet lo 215-351-2799 or ntail the answersheet to Member and Customer Service, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106 1572, using the courtesy envelope provided in your MKSAP 18 slipease. You will need your 19 digit onder number and 8-igit ACP ID nun ber, which are printed on your packing slip. Pease allow 4 0 6 weeks for your scare report to be emailed back to you. Besure to inchide your email address for a response. you do not havea 10 digit order numberand 8 digit ACP ID number, or f you need help creating a user-name and password te access the MKSAP 18 online answer sheets, go (o mksap.acpoaline.org or email custservw acpontine.org Disclosure Policy (ts the policy of the American College of Physicians (ACP) co ensure balance, independence, dbjectivty and scientific rigor In all of fs educational activites. 7 his end, and con sistent with the policies ofthe ACP and the Accreditation CCourel for Continsing Medical Fducation (NCCMF), con- Uributors toall ACP continuing medical elucation activities are required to disclose all relevant financial relationships with any entity producing, marketing, r-selling or ls: {ributing health cate goots oF serves consumed by, or used on, patients, Contributors are required to use generic pamesin the discussion of therapeutic options and are required to derail any unapproved, off label, or investigative use of commercial products ar devices, Where 4 trade name is used, all available trade names for the same product type are also included. If trade-name products ‘manufactured by companies with whom contributors have relationships are discussed, contributors are asked to pro vide evidence-based citations in support of the discussion. The information is reviewed by the committee responsible for producing this text. necessary, adjustments to topics orcontibulors’ roles in content development are made to balance the discussion. Further, al readers of this text are asked to evaluate the content for evidence of commercial bias and send any cekevant comments to micsp editors acponiline.org so thal future decisions about content and contributors can he made in light of this information Resolution of Conflicts To resclve all conflicts of interest and influences of vested interests, ACP’s content planners used best evidence andl updated clinical care guidelines in developing content, ‘when such evidence and guidelines were available. All content underwent review by peer reviewers nol oa the ‘committee to ensure thal the material was balanced and unbiased, Contributors’ disclosure information can be ound with the list of contributors names and those of ACP. principal staff listed in the beginning of this book. Hospital-Based Medicine For the conventence of subseribers who provide caren hospital stings, content that fs specifi to the bospltal suiting has been highlighted in blue. Hospital icons (2) highlight where the hospital-only content beyins, continues over nore chan one page, and end High Value Care Key Points Key Points in the text that relate to High Yalue Care con: ‘cepts (that is, concepts that csscuss balancing clinical ben- ‘fit with costs and harms) are designated by the HVC leon HVE. Educational Disclaimer ‘The editors and publisher of MKSAP 18 recognize thatthe development of new material offers many opportunities {or error. Despite pur best efforts, some errors may persist in print, Drug dosage schedules are, we believe, accurate and in accordance with current standards. R advised, however, to ensure that Une recommended dosas in MKSAP 18 concur with the information provided in the product information material. This fs especially Important Imcases of new, infrequently used, or highly toxic drugs. Application of the information in MXSAP 18 remains the professional responsibility of the practitioner.‘The primary purpose of MKSAP 18 fs educational Information presented, as well as publications, techno- ‘gies, products, and/or services discussed, s intended to {inform subseribers about the knowledge. techniques, and experiences of the contributors. 4 diversity of professional opinion exists, and the views of the contributors are their ‘own and not those of the ACP. Indusion of any matertal in program does not constitute endorsement or recom: mendation by the ACB. The ACP does not warrant the safety, selabllly, accuracy, completeness, or usefulness of and dls claims anv and all ability for damages and claims that may rewill from the use of information, publications, technolo sles, producis, andor services discussed in this program, Publisher's Information Copyright © 2018 American College of Physicians. Al sights reserved, ‘This publication is protected by copyright, No part ef this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic or ‘mechanical, including photocopy, without the express con sent of the ACE. MKSAP 18 Is for Individual use only. Only fone account per subscription will be permitted for the pur pose of earning CME credits and MOC points and for other authorized uses of MKSAP 18, Disclaimer Regarding Direct Purchases from Online Retailers (MBandéor MOC for MKSAP 18 fs available only Tyou par chase the pmgyum directly ftom ACR. CME credits and MOC points cannot be awarded to those purchasers who have purchased the program from non-authorized sellers such as Amazon, eBay: or any other such online retailer Unauthorized Use of This Book Is Against the Law Unauthorized reproduction ofthis publication is naw The ACP prohibils eeproduction of ths publica! ofits parts ia any form cther for individual use or for distrbution on orany The ACP will consider granting an individual permission lo reproduce only limited portions of this publication for lhls of her own exclusive use, Send requests in writing to MKSAP# Permissions, American College of Physicians, 190 N. Independence Nall West, Philadelphia, PA 19106 1572, or email your request to mksap editors @acponline org. MKSAP 18 ISEN:978 1.938245 47.3 {Endocrinology and Metabolism) ISBN: 978-1-938245-54-1 Printed in the United States of America. For order information in the US. or Canada call 800- ACP. 1015. All other countries call 215-351-2606 (Monday to Friday, 9 aol 5 PM 1), Fax Inquiries to 215-351-2799 or email to custserv@acponline.org. Errata Frrata for MKSAP 18 will be available through the MKSAP_ Resource Site at misap.acponline.org as new information becomes known to the editars,Table of Contents Disorders of Glucose Metabolism Diahetes Mellitus, Screening for Diabetes Molicus Diagnostic Criteria for Diabetes Meliitus Classification of Diabetes Meditus. Management of Diabetes Mellitus Drug Induced Hyperghvcemia. Inpatient Management of Hlypenglycemia Hospitalized Patients with Diabetes Mellitus. Hospitalized Patients Without Diabetes Mellitus Acute Complicattens of Liaoetes Melitus Diabetic Ketoacidosis/Hyperglycemie Hyperosmolar Syndrome: ‘Chronie Complications of Diabetes Mellitus Carciovaseulur Morbidity Diubeuic Retinopathy Diabetic Nephropathy Diabetic Neuropathy Diabetic Foot Uleers Hypoetycemia Hypogycmia in Patents wih Diabetes Malus Hypoglycemia in Patients Without Diabetes Mellitus, Hepoglvcemfa Unawareness Disorders of the Pituitary Gland Hypothalamic and Pituitary Anatomy and Physiology Pituitary Abnormalities Incidentally Noted Pituitary Masses Fimpty Sella ‘Other Abnormalities ‘Mass Lffects of Pituitary Tumors. Esaluation of Pituitary Tumors. Treatment of lnially Nonfunctioning Pituitary Temors Pituitary Hormone Deficiency Panhypopituitarism, Adrenocorticotropic Hormone Deficieney (Secondary Corusol Deticteney) Thyroid: Stimulating Hormone Deficiency. Gonadotropin Deficieney 18 20 20 2 » 23 2s 23 26 2% ” 28 28 » 29 30 30 31 32 Growth Hormone Deficiency’ Central Diabetes insipidus Pituitary Hormone Excess yperprolactinemia and Prolactinuma Acromezaly ‘hyzeid Stimulating Hormone Sccteiti Turnors Excess Antidiuretie Hormone Secretion Excess Adnenocorticoiropic Homone ‘om Phuuiary Souree (Cushing Disease) Disorders of the Adrenal Glands Adrenal Anatomy and Paysiclogy Adrenal Hormone Excess Cortisol Excess (Cushing Syrsinome Due to Adrenal Mass) Primary Aldosteranism Pheochromceytoma and Paraganglioma Androgen Produchyg Adrenal Tumors, Adrenal Hormone Deficiency Primary Adrenal Insuificiency Adrenal Funetion During Critical ines Adrenal Mass Incidentally Noted Adrenal Masses Adrenocortical Carcinoma, Disorders of the Thyroid Gland Thyroid Anatomy and Physiology ‘hyroid Exam structural Dsorders of the Fayroxd Gland Thyroid Nodes Goiters Thyroid Cancer Evaluation of Thyroid Punetion Disorders of Thyroid Function. ‘yreid Iormone Excess ((lyperthyroidism and Thyrotoxivoss). ‘Thyroid Hormone Det seney Drug Induced Thyroid Dysfunction Thyroid Function and Dystunetion in Pregnancy Nonthyroidal llness Syndrome (Euthyroid Sick Syndrome) 36 36 26 38 0 2 2 45 15, 15 46Thyroid Emergencies sstppaegeases oo ‘hyrvid Storm est eaMhecabesuNSi89 Myyedema Goma, 60 Reproductive Disorders Physiology of Remale Reproduction a ANCOR cccasconmamnacenunnescscans one 1 nical Featnres a valuation of Amenorrhea 62 Treatment of Amenorrhea Hyperandrogenism Syndromes. Hirsutism ard Polyeystie Ovary Smnrome. Female Infertility, ‘hysivlogy of Mae Reproduction Hypogonadism Causes. = deeiavercvavesiess66 (Cine Features 66 valuation Management ieseievensuns by ‘Ansbolle Steroid Abuse in Men ss. ccs secveecs esse s68 Testosterone Changes in the Aging Man... 4.0.4. 68 Male infertility 6 Gynecomastia 68 ‘Transgender Hormone Therapy Management Calcium and Bone Disorders Calcium Homeostasis and Bone Physiology Hypercalcemia : 2 Clinical Features of Hypercalcemia ‘Causes and Diagnosts of Hypercalcemia Management of Hypercalcemia. Hypocalcemia lineal features of icpocalcemia Causes and Diagnosis of Hypocalcemia Management of Hypocalcemia Metabolic Bone Disease 2 low Bone Mass and Osteoporosis Vitamin D Neficieney Paget Disease of Bone ography Self-Assessment Test. Index 176 7 a a n n % % % % 76 al pall 282 arEndocrinology and Metabolism High Value Care Recommendations The American College of Physicians, in collaboration with multiple other organizations, is engaged in a worldwide initiative to promote the practice of ligh Value Care (HVC). ‘The goals of the HVC initiative are to improve health care ‘outcomes by providing care of proven benefit and reducing costs by avoiding unnecessary and even harmiul interven tJons, The initiative comprises several programs that inte gate the important concept of health care value (balancing 200ma/al. (mmo Festina plasma glucose? <100 maa. 100-125 mall D126 mole Bommolt) —(54-49mmol/l) (7.0 meal) 2Hour placa glucoreduring mOGT® 140 mala 10-199 mala 2200 mat. TBmmoll) — (71.0 mmoll) (IT mmol) Hemoglatin ,, 9% 5.7% 6.A% MS G2 mmolnel) (39-46 mmovmolt (48 mmol/l to sbana Llypecanic ete ve atom fing pa aot OGT eames shld cn ‘orient ee denarate nonin a Re ettan isboms oe Diabetes Connsand Comphonian allOCCT say nn ams ‘Beingplao glcone 3 Pao saaaral presence of autcantibodies [ndividuals with idiopathic type | diabetes may develop episodic DKA. There is typically a strong, ‘amily history of type 2 diabetes in persons with idiopathic diabetes, andit ismore common in Asianand African American patients, particulary with sub Sharan African ancestry Acquired Type 1 Diabetes Mellitus eta cell destruction may ocour from diseases affecting the pancreas or from theefiect of drugs or infections (see ‘able ), This may result in impaired insalin production or secretion swith the subsequent development of type I diabetes. Insulin Resistance The ineffective use of insulin by the peripheral cells to utilize shucose and fly acids charucerizes msulin resistance, Blood shicose levels temain in the normal range aslong.s the beta cells, ean increase insulin production. Hypergiycerna results from 9 relate insulin deficiency when the pancreas can no longer pro duce enough insulin, Obesity increases the rk for iasain resis ance, which isalsoa component of the metal syndrome and predisposes to thee development oftype2 diabetes Metabolic Syndrome ‘Metabalicsyndrome comprises constellation of sk factors for development of type 2 diabetes and CVD, which inciudes abdominal obesty: impaired glacese metabolism, hypeelipi emia, and hypertension. Muluple organizations define ravd [70 ml dao avons eiceres moporinane3 ren peta etch nar metabolic ynclrome differently (able), The Endre Soviety recommends screening patients with risk factors for mclablic symdrome every 3 years fo evaluate fasting plasma suc, fst ing, lpi panel, blood pressure Calculation of the 10 year cardiovascular ris, using cither the Framingham Risk Soore or the American College of Cardiology {ACCYAmerizan Heart Association (AH) risk eal. sree ‘ommended for patients with merabolie syndrome. and waist cirenmerence Type 2 Diabetes Mellitus Most cases of diabetes (90% 10.95%) meu! the erteria or type2 labetes.iyperglycemi aecompanied by insulin resistance or relative insulin deficiency defines type 2 diabetes, The extent of eta celldysfunction determines the degree of hyperglycemia, ‘which may worsen over time wth progressive decrease In inst lin production, The pathoenesisoftype2 diahciesisrmltifacto, rialwith influence from both genetic and cavirenmental faciors Iype 2 dlaberes is commoniy’ present in fist cegive relatives pf both individuals at high risk for or diagnosed with type 2ciabe tes, There is aloo on inereased risk in sever eianicities ined Ing: Hispanic/Latino, African. American, American nlian, Asian American, Addivoral risk factors for diabetes risk include incressing age and decreased physical aetiily Type 2 dlabetes classically presents in adults, although there is an inereased incidence among children and adales cents as the mte of everweight obesity inereases in these pop. lations. Type 2 diabetes has a gradual onset with most 2Disorders of Glucose Metabolism Dieadvantagee | Memociobin A, Convenient Does notraquitafasting and no Lower sensitnty beciaanatie compared with FPG or | recticions on callactiontine 2hePG | ‘Notalered byillnes, tress, ee Erroneous increases ordecreases in hemoglobin A, result secondary to factors affecting erythrocyte Mosewer blood glucose concentration over the prior 8-12 meake. sua": Iron dafciency anemia Blood lossthemolysis ‘Minimal biological aratilty ‘Blood sample remain table | Standardized assay Kidney dicaase Testaccuracy’& monitored Liverdisease Pregnancy Measurement cordate wih micrvaseuar and rnacrovosculroutearnes Heroalobin variants iningvials wit Affian, Southeas Asien and Medreraneashertoae® Higher value inblack corpared wit non-Hispanic vite posers” | | Alected by some glucose ¢ phosphate dehydrogenase vrarise Unavalablein some areas ofthe world Expensive Inexpensive Inconvenvent: 2 Shaur fasting required anc restction ontine-ct cllectan Aocte dt byillres Mezsures single pointintime Wieily avaiable Automated assay roe High biological variabiity within pationt Blood sample unstable ater collection Diam varition Diabetes complications natascloselylinked to FPG compared with hemoslebin, Sample source (capillary, venus ar aerial blood) | alters the measurement Assay tandardization incomplete ZhePG curing Highly sensitive o detect rakot developing diabetes _Smlar dsadvantagesasFPG test | oct Detects eatly abnormalities in gluesze mataboliem Prolonged patient preparation Riskot hypoglycemia at 4-6 hours in normal persons Poorreprodusiblity Expensive emerfte hy hgh mba ang ir id pen hc atl Dean i Fgh et Eo Con Aaj Cte Ataiton 2. Cian ae noo att: Stef Mesa Cate Date-2018 Diabetes Cire 20111519597 treo aaa ta mic kets stan yoni te Sh Mec Carin Dade 201. Dba Car 21S SH PMD 2222377in Deficiency" Immune- mediated itype 14) Typo dissotos 4 Bae forme "eff man’ syncrome antinauln recoptoranibodios pathic (type 18 Acauired Diseases of the exocrine pancreas: pancreatitis, raurna/ ‘pancreatectomy, seopiasa, cystic libres, hemochvomatoss, ‘ibrocalculovs pancrestopathy ‘Drugelatec: Vocorlrt poor), nvavenous pentamidine ronegative) Infocions: congenital nibala, enteroviruses Insulin Resistance EE es aaa “ype Zalabetes? i cae ‘Other or Rave Types Genetic defses in beta-cel function (nluding sixcitinct MODY synckomes} rete defects in insulin action Endocrinapnthies: Acromegily, Cushing syrdrome, lucagonoma, pheochromocytoma, hyperthyroidism’ Sematertatinoma aldostaronoma! Drug related Glucocorticid,thissdes, B blockers daconide, tarolinns, yclomporne, niacin, HV protease ithibitors ype mtipsychaties clozapine, olaneapire ‘Geretic syndromes: | Deeonieee! | WiotFam syndrome OIDMOAD)® | | | | linefetter Turner anc Feeder syncrames: myotonic aystrophy affected persons remaining asymptomatic for several years. At the time of diagnosis, these patients may already have micro vascular and/or macrowsscuilar CVD. Although the beta cell Disorders of Glucore Motaboliem does not produce suficient insulin to overcome insulin resist ance and maintain euglycemia, theres adeemate insulin pro duction to suppress lipolysis and. prevent DKA in pe 2 iabetes. DKA in type 2 diabetes may rarely occur in the set Lingofestreme strss or illness The development of type 2 diabetes in high-risk individu alscan be delayed or prevented with modifications ro lifestyle (diet, exercise), pharmacologic intervention, or metabolie sar gery: The goal of these interventions is welght loss and the reduction of insulin resistance. In the Diabetes Prevention Program (OPP), lifastele modifications reduced the ineidence of type 2 diaketes in persons with prediabetes by 58%, Thus the ADA recommends the DPP goals of 7%. weight loss over 6 mnths anil at least 150 min week of maderate intensity exercise to reduce the Fskof diabetes development, A diel rich Inmonounsaturated fa, wholegrains, vegetables, whole fruits, and nosis revommended. Several pharmacologic interventions have demonstrated efficacy in diabetes risk reduction (Table 6). Safery data, cost, sind long. term durability of each iniervention must heconsid ‘ered for each individual patient, Metin reduced the inet nee of diabetes by 31 compared with placebo in the DPP In auidition metformin hus long term safety data, The ADA and the American Association of Clinical Endocrinolegists (AACE) recommend metdormin intially fordliabetes risk prevention it individuals with prediaetes. particularly in those with inexeasing hemoglobin A, values despite lifestyle modifica tons who are yemmnger than 60 years of age, are obese, or have «ahistory of gestational diabetes, ABEND S ica Aeconting to the Diabetes Prevention Program, ifestyle ‘modifications, inclading weight loss, healthy det and exercise, reduced the incidence of type 2 diabetes in persons with predlabetes by 58%, + The American Dinhetes Assoniation (ADA) and the American Assoetation of Cinical Endoerinolagists |NACE) recommend metformin initially for diabetes risk prevention in individuals with prediabetes, par viculary in those with increasing hemoglobin A, values despite lifestyle modifications who are younger than 40-years of ae, are obese, or havea history of esta ional diabeies, Ketosis-Prone Diabetes Mellitus The term “ketosis prone diabetes” glycemic syndromes also known as ketosis prone type 2 cia betes, “Fatbush diabetes.” type 1B diabetes or atypical dlabe fe. Thee syndromes present with episodie DKA resulting from insulin deficiency but have variable periods of insulin dependence and independence. For individuals with KPD, insulin therapy for the treat ‘ment of DKA is required until DKA has resolved and the beta cells are no longer impaired by glucose toxicity, if possi ble, and ean producessuificient amounts of insulin to suppress KPD) incorporates SeveralDisordors of Glucore Metaboliem SIME | Qualifying Criteria. NCEP ATP ill 2005 International Diabetes Federation (2006) (Mests at Least 3 of 5 Criteria) (Required Central Obesity and at Least 2 of & Remaining Criteria) Wise creumference Men'240)in (02cm) Europies Festing TS HDL cholesterl el pine | Festingglucste Women 235in(88 om) 2150 mgAlL (17 mmovt}. Drug therapy testing incseased TG Men <0 mg/d. (1.0mmol4) Women SOmg/di 13 mmalil}or Drug therapy targeting dacresses HDL cholesterol Syetolie>130 mmitg Diastolic 285 mmitg or Drug therapy for hypertension Blood glucose 2100 ma/dL or Drug therapy for increased ghcose Mon 37 nem) Women a(€00n) Sou sans Men 235in(90 en? Women 23 (800m) linea Nen235in(90 on? Woman in (em) Jepanese Non 335in(90 en Wonen23 n (0 cm) Sonh/cerara americans Men23Sin(90.mp | Women 231 n(€0 om) | SuleSahann fice Men 237in(94en) Wnen 3 in (em) Eastern Madoranean and Middle Eas on 337 ni94.cm) Worn 231n(€0 cm) 2509/6 (1.7 mrcindor righ ea ecraeed TG Men 40 mgid{0 mel | Women <50 mg/dl (1.3 mmol/L) or | Dee eceaeeeelecemenll| 2120 mel | Diva therapy hypertension’ | Blood glucose 2100 ma/dl or | ‘ean ear easton, Won Hs eens sta ater Socorro croateator he Dea en [Ey ints se tne arte tinea course exited wih KPD, uncertainty prevails egarcing th 1d long, term insulin treatment regimens. Four classification stems have therefore been developed to provide predicive cnt rata Dates Felon. Te DF costes i Feroucee rd moeconans wine att peed for short term fuidance.on the length of insulin therapy: A longitadinalstady 96% and insalin de DKA with the Afi system when compared to theather classi cation systems, with a sensitivity of 99° ge en ie eto wnt 0 wom cen mn | demonstrated greater accuracy in predicting heta cell reserve sndence 12 months afier the initial episode of andl specificity of With the AB system, autoantibody status (A) andEffectiveness Detard exerciser ‘Shountodelay onset of labetes by upto 10-20 years Modesty ofecive a ong a2 itdowsnce cause weight gars Smoking casstion bbutis abways rocommmendes Bariatric surgery Effective used in morbidly bese pesscns eMl>40) Metionnin Showntodelay onset of siinbetes by upto 10 years Showntadelay onset of diabetes upto years Loase inhibitors ovistat) eGhicosttaseinnibicars (cearboze,vogibose) Thiaroidnediones (woghtzone, rigleazone, oalitazone! (Gucagon tke peptide (GLP) receptor agonstslexenatide, Shown tocelay onset of diabetes upto years Showntodelay onset af dighetes upto years Signticane weight lessand improvementsingilyeerne ‘raglutde) contol inhigh risk personsin shortterm studies lectin and inulin Inatfacive secretagogues (sulfonjlueat, oglitinides) | ACE inhiitorsand Inatfocive angiotensin receptor Backers Exrogen progestin Modest eect only ErGostinleniss ond American Cole of Eodouinalony en the eorerchensie {pe abet range’ nga 101 Exc Sora Es Pa Miser al pa ea) beta-cell function (B} are key determinants affecting whether nindivihal will require long, (erm insulin, Longitactinal dats from KPD cohorts indicate individuals without beta cell reserve regardless of the antibody satus (A'f and A) are more likely have poor glycemic control and dexelop leng term insulin dependence ater the development of DKA, com: pared to ineividuals with preserved beta-cell function. Gestational Diabetes Mellitus An increase in insulin resistance during the second and third trimester of pregnancy i a normal physolyse pheromencn driven by placental hormones. With impaired beta eel function, insulin production will be inadequate to overcome the insulin resistance with subseqaent development ol hyperglycemia Gestational diabetes defined as hyperglycemia during the second of third trimester in women without a prepregnancy iagnosisoftype Tortype? diabetes Risk factorsinclude age over 25 years, overweight /civesity, amily history of type 2 diabetes, Disorders of Glucose Metaboliam and high rik racial/ethnic groups (blacks. Hispanic tino Americans, Southor Fast Asians, Paci Islanders, and American Indians). Acverse maieral and neuntal outcomes related 0 gestational diabetes Increase with worsening. hypenslsceria, Complicationsinelude macrosoria, labor and delivery complica tions, preeclampsia, fa defers, necnsatal hypogiycemta, spon, taneous abortion, and inirauterine fetal demise. Given the increased prevalence of undiagnosed type 2 dia betes in te general population, de ADA recommends standard screening for any pregnant woman with diabetes risk factors the inital prenatal vist. Women with hyperglycemia identified during the frst umester ane lassie 2s having ype 2 Uaberes instead of gestational diabetes, For all other pregnant women ‘without a prior diabetes diagnosis, gestational diabetes sero Ing should occur beiwween gestation weeks 24 and 28. The screening method! recommenced varies among expert groups, The “one-step” OGTT involves blood ghicose measurements at baseline (sting) and 1 and 2 hours after 2.75 4, oral glucese. load. One abnormal value above the ext-point Is diagnostic of festational diabetes. The “two step" OGTT jnvelves am initial blood glucose sncasusement 1 hour afer a 30 g OGFT 1 blood glucose is sbnormal, the second step i initiated. Glucese is measured at aselne (fasting) andl 1. and 3 hours after a 100-g oral glucose load. Two abnormal blood glucose values, after the 106-g load are diagnostic for gestational diabetes. Most women with gestational dighetes have ghisose nor smulization after pregnancy, but they are at an increased rsk for dewlopment of recurrent gestational diabetes and type 2 diabetes. The ADA recommends a 75 @ OGTT 4 to 12 weeks postpartum to confirm resolution of hypenglyceria. 1 the initial postpartum screen fs normal, life long. screening hy Conatinue every 110.8 years with a7 gOGTT. hemglohin A. or fasting plasma glucose Uncommon Types of Diabetes Mellitus Genetic detects impairing either insulin seeretion or insulin action are rare forms of diabetes melts (See Table 4), Maturity-onset diabetes ofthe young (MODY) is characterized as an ouosomal dominant monogenetic defect on diferent chromosomal Joct resulting, in six subyypes defined by the specific gene affected. Although inswiin aetion remains nar mal in MODY, glucose sensing and insulin secretion are altered, Autoantibodies are absent. Indivkluals with MODY present with aclinical course thatis frequenthy atypical ftype Tor type 2 diabetes. The onset of symptoms occurs before 25 years of age, an there by typlcally astrong tau history of atypical diabetes in nonobese patients. Excess hormone production associated with several ennicerinopathies can also impair insulin secretion or insul action inducing hyperglycemia (see Table 4). Management of Diabetes Mellitus Effective diabetes management is best achieved through a patient censered approach with patients and their caregivers, developing individualized goals and treatment plans 7Disorders of Glucose Metabolism compatible with patient preferences, lifestyle requirements ‘comorbidiies, and safety Management should also income on, self monitoring of blood glucose, fe atons, and pharmacologic therapies, HCO ital cl a + Effective diabetes management requttesa pattent centered approach that individualizes goals and ‘treatment plans, taking into consideration unique (characteristics ofthe patient and patient preferences, Patient Education Diabetes self management exlucation and support (DSMES) provides the knowledge and skills for patients to perform diabetes related self care and develop effective problem solving strategies. The ADA recommends consideration of referral for SMES at several critical periods in eare: st ime of lagnosis, annually to reassess needs during care transitions, and when self management skillsare impacted by health sta~ tus changes. SMES has been shown ta improve outcomes, such as hemoglobin A,, and quality of IH, and alsy recive costs, as patients are able {0 reduce utilization of acute eare and inpatient faelities for dishetes management Self-Monitoring of Blood Glucose Self monitoring of blood glucose (SMBG) isrecommended for patients on intensive insulin regimens (multiple-dose insatin regimens or insulin pump therapy). Specific regimens for MBG monitoring are individustized and may inelude prior 10 ‘meals at betie, before and after exercise, and before opera tion of machinery: SMEG may be used fo deel and correct haypoglvecmia. SURG may be informative when preprancal blood glucose values areat the target goal, but the hemoglobin A, fsabore goal. Measuring postprancial blood glucose levels may identify undetected! hyperglycemia, In motivated patients on nonintensive insulin regimens, SSMBG can be considered: however, the optimal testing tre ‘quency has nat been determined in these patients Hemoglobin A, generally correlates with averages: month ‘blood glucose level in patients without hemoglobinopathies or inereaved enythmeyte turnover, therefore, treatment efficacy ‘can be measured by combing SMBG and hemoglobin 4, data (Tabie 7 and Table 8) Another option is a continunus ghicose monitoring ss tem (CGMS), which ean alert the user to retrospective and, current tends of hypoghcemin and hyperglycemia. In adi ton, the FDA has apprevedl «CGMS for real time insulin dos ing as well as monitoring, The goals in using a CGMS are (0 improve diabetes care by lovering hemeglobin A,, and avoxd ing hypoglycemia, which is critical for those with hypogivee mic unawareness. The ADA endorses CGMS use in adults (18 years of age) with type 1 diabetes who are noi meeting, salycemie targets. The Frdocrine Society endorses the use of CGMS in patients with type 1 diabetes with an elevated hemo. globin A, of an A,, level at goal when worn daily, since data 8 demonstrate improved glycemic control with longer duration OfCOMS use. Inthe fuse, CGMS may be indicated for pationss with type? diabetes on intensive insulin regimensas well * Self monitoring of blond glucose ¢ 4 continuous ‘ease moatioring systems recommended for patients on intensive insulin regimens (muliple dose insulin regi -mens oF insulin parp therapy) Recommended Vaccinations and Screening, Persons with dlabetes should receive age appropriate vaccina tions as recommended by the Advisory Committee on Immunization Practices quidclines. Adlitionally, patiensswith abetcs should recelve Influenza vaccinations annually, the pneumococcal polysaccharide vaccine (PPVS23), and the series of hepatitis B vaccinations. The CDC's recommended immunization schedule can be reviewed at: bups:/vewwede. sow vaccines/sehedules ep imac Nonpharmacologic Approaches to Diabetes ‘Management | ese changesare essential for the long term management of diabetes and prevention of cardiovascular complications: While ‘theyshnnld beindividualized, diet and phrsiealactivity are crit ‘cal components for patients with type Land type diabetes Medical nutrition therapy with a registered dietitian pro ides individualized dlabetes-speeifc education to promote healthy diet choices to achieve glycemic goals and weight ‘management anil has also been associated with reductions hemoglobin A,, 1h patients with (ype tand type 2 diabetes. The ADA does not recommend a specific diet: however, in over ‘weight and obese patients with type 2 diabetes, a goal of at least 5% weight fos is recommended and has beer shown 0 improve glyvemie control Physical activity resommendationsare thesame as these of the DPP program: moderate (0 vigorous Intensity aerobic activity for 150 minutes/week, vigorous intensity aerobic activity fr 75 minutes.weck, oF a combination of both. This thas been shown to reduce hemoglobin A,, decrease weight improve a sense of wellbeing, and improve CAD risk factors Resistance training # recommended two oF more times per week. Older adults with diabetes should engage in flexibility and balance training two Lo three times per week, irpossible. Prolongeel sedentary behavior should be interrupted at $30- minute tervals with light activiy or standing. Weight lossmedications or metabolicsurgery are alterna: tive options to consider medical nutrition therapy znd physi cal activity aze unsuccessful (ee MKSAP 18 General Internal Medicine), Metabolic sargery should be considered in obese persons with type 2 diabetes, Significant weight loss ané Improvements in glycemic control, including diabetes semis, sion, can oecur postoperative. ‘Additional factors to consider and adress in-patients with diabetes mellitus Include anxiety, depression, andSate of Bedtime Hea Capillary Glucose Healthy Earyindiscace course Few comarbidties BOADmgd <1 maleke foreclet (44 72mmal) (10.0mmoV Preconception eae Fatort peoforencs Le expectancy >10yeats Conlin Signifcant comobictiosincudingodionced —-<8.0% Health athorsclovecior merovemslarcomplications "65 Longer duration of dhadeteswth city Zchiewng glycemic onlsdesete Sppteprntemarngtnt Frequerthyooalcemia Hypoglycemia unawareness Life expoetancy e10yenrs Cle Healy o3% yor mga 20.180 9/4 dul a Seva (so72mmore) Sessmmoly aended lie expeciancy Noimpatmert of cognition or function Complev/imermedare 20% 30.150 meio 100-120mprat Multiple comerbisices (S083mmery (5.6-10.0rrmov1) Hypoobyemia is Fall Mutipleinsrumenral ADLimpoiments Mi o-mocerateimpaimentin eoiton Yerycomplenpoor neath 5% io0-1e0mg/et npzi0 mea. Ged areenialceraneeoaey (58-100 mmol) feta mmovt) Long-term cate placement Noderteto severe impairnentin cognition Mutiple ADL dependences Lmitad lie expectancy Prognart Pressing ype !dabetes,preesstingtype 606.5%, Faring 95mg/ol —_-hourpasspena women! 2dabetes, of yestaionalcisbetes fnitiousevere (33 mmol) s10ma/a Iypogyerrio aun} (<60% mayne or eptrnel az 2-hovr postprandial s120my/at ren "AB ais dae tment he atts caine rarer moaranmetrronentnreoer coal oe rem arnn When ees seopegpon karan amon, gate cos. and vase koors cv sy be mde bar ha chard you ina ane nga lemon hobo ‘eared aalgncustotbnnd ty Sent manasa anger eee mou Petoe nd pracy orp a Head A, sommes be eed Stan comida ars ath anon dens aber mio. itso dee ‘Prd salaries incense ld ny diel hc ae na A alan een hi bd rommentns or Aros sin 6 Gh rl S55 Sk nao 20202577 Avomencnon To Aner oes Asoo, Chas: Str of Mel Carin Dabs 2018 Dabs Care 2084 ap IS1195125 MD: 202238)|Estimated Average Estimated Average Plasma Glucose Level PlasmaGlucose Level mgldl (95% C1) ___ mmol/l (95% CH) é 126(100-152) 7055-85) 7 194(123185) 8.6(68-103) 8 193(147.217) 102081121) ° 212(170249) 118194139) 10 200(193.282) 73.4(10.7-15) [av 269 (217.314) 14.9(12.0-17.5) 2 298 (240047) 165(13.3493) 1 A Shean rager: Sardar Niece Can Bint 2018 Dots Cre 201641568 Sa as reir | diabetes related distress. Screening, for pyychosnctal issues and behavioral health conditions should occur at the time of diabetes diagnosis and periodically. These conditions can adversely affect gheemic control dirccily and through chal: lenges with patient adherence to management plans. Pharmacologic Therapy Pharmacologic therapy should be individualized taking into consideration person’sage: state of health, weight, the patho physiology of his/her hyperglycemia, specifie rsks/benetits of 1 potential therapeutic agent, medication cos, and the per som’ lifestyle and personal treatment goals, The hemoglobin A, soalsare generally not stringent in patients with significant ‘comorbid conditions, macroxascular CVD. short life expec taney; long duration of diabetes, limited resources and soctal support, low health iteracy imumeriey, nonadherence. and at high sk for coryplications foam hypoglycemia. Most clinical practioe guidelines, including the ADA, recomment target hemoglobin A,, thresholds hase cn a patients sate of health (Gee Table 7). In contrast, the V\/DoD guidelines for the man agement of type 2 diabetes recommend a hemoglobin A,, ta sgt range instead of a target threshold, The VA/DoD guidelines atterupt to avoid intensification of pharmacologic therapy tasedsolely upon marginal changes in hemoglobin A, caused by known patient characteristics and laboratory limitations tay could potentially cause greater barm than benefit in ind viluals with major comorbidities, microvascular complica tions, or advancing age. The American Collegeof Physicians (ACP) recommends hemoglobin S,, level between 7 an! 8% in mest patients with ype 2 diahetes and clinicians should consider Geintensifying phormacckogie Herapy in patients who achieve hemoglobin 4,, levels less than 6.5%, The rationale for these target is baset ‘on evidence that callectively shows treating to targets of less than 7% compared with targets around 8% did not seduce death or macrovascular events ever abana 51010 years of tre: ment but did result in substantial harms. Mote stringent targets may be appropriate for patients who have a long, life ‘expectancy (-15 Years) and are Interested n-more intensive alyeemic conirel with pharmacologic therapy despite the risk for harms. including but net limited to hypoghemia, patient bnrcden, and pharmacologic costs. ACP also recommends avoiding targeting an hemoglobin A, level in patients with a Hite expcetaney fess than 10 years due to auvancel! age (80 years or olden, residence in a nursing home, oF chronic ‘medical cunditions because the harms outweigh the benefis 4 Us population: Several hindmark studies provide guldhnce on giycemic pealsand CVD risk reduction. Intenshveglveemiecontrol com yparedl with standard contol significantly reduces the ine! denive and progression of microvascular complications in patients with type J and (ype 2 diabetes, as cemonsirated by the Diabetes Control and Complications Trial (DCCT) aad the UK Prospective Diabetes Study (UKPDS. Long term follow updemonstrated continued redaesionsin microvascular com plications despite comergence In glycemte contr! between the study arms, Action to Control Cardiovascular Risk in Diabetes (ACGORD), Action in Diabetes and Vascular Disease: reteraxand Diumlcron MR Controlled Evaluation (ADVANCE), and the Veterans Affairs Dfabetes ‘Irtal (VADT) further rein forced theaswoctation of reduced microvascular complications. ‘with tight glyeeme control, but also ngghlighted that patients and providers must balance the risks/benefits of a labor intensive regimen with the potential morbidity and mortality in specific populations. Long term follow up eciluation Of paticipanis in the intensive insulin arms of the DOCT and UKPDS trials who ‘were cary in the course of diabetes demonstrated a significant reduction in CVD and mortality. In contrast. ACCORD, ADVANCE, anid VAD" evaluated tight glycemic control in alder perwns with more advanced Iype 2 diabetes and preexisting, CVD oF CVD risk Eactors. CVD was not significantly reduced in the ACCORD and ADVANCE tras, YADT demonstrated sig nificant reduction in cardiovascular events, but no change in candioaseular or ove Recently, the controlled trial (RCT), found that in patients with established CVD. empaghiflocin, asodium glucose etransporter? (SGT) i mortality. MPA REG Outcome trial, a randomized Inhibitor, redaced! the campostie outcome (Cardiovascular death, nonfatal myocartial infarction, or nonfatal stroke); it ‘vas primarily dziven by si rates of caruiovascular death by 38%, There was aoa signif cant redaction in all-cause mortality by 32° and hospitaliza, tion for heart failure by 25%, Ws a result ofthis trial, empaglt flozin received FDA approval for reduction of cardiovascular death in adults with type 2 diabetes and CVD. Another SGLE2, inhibitor, canagflacin, also demonstrated a reduction in ear diovascular events. bul not cardiovascular death, In patients swith type 2 elahetes a high risk for cardiovascular disease when compared to placebo in the CANVAS (Canaglilazin, Cardiovascular Assessment Study) Program, ffeunt relative risk: meduetion inThe Liraglutide iffect and Action in Diabetes: Evaluation ‘of Cardiovascular Outsome Results (LEADER) NC inctuded subjectsat risk for CVD anc found that kragltide, glucagon like peptide 1 (GLP 1) analogue, significantly reduced the pti mary composite outcome (cardioascular death, noniatal Ml, ‘or Ponfaral stroke) by 13% cumpared! with placebo tretatne risk reluction). Liraglutide also significant reduced cardinascu ler death (22%) and all-cause mortality ((54) relative to pla yperglseemia, This ean be accomplished with sabeutancows Insulin injections, inhaled insulin preparations, er continues ‘subcutaneous insulin infusions (CSID with gn instlin pump. Initial total daily iasalin dosing ranges frcan 0.4 to 1.0 U) ‘g/day in patents with type diabetes. Basal Insulin typically encompasses approximately 50% of the tutal daily dase of insulin, with prandial insulin covering the remaining 50% ‘The avalale insulin formulations and their acuvity profiles aresummarized in Table. ‘The timing and mode of prandial insulin delivery varies based om pattent needs preferences and dietary habits. MDL prandial dosing can be accomplished with fised-dosing, car bobydrate counting, or modified carbohydrate counting. In general, | unit of insulin avers 10 10 20 grams of eurbohy dates consumed, A modified carbohydrate counting method ‘can be use when the rom oF eazbohydrates consumed ean pot be accurately Counted. With this method, regular oF an logue insulin doses can be adjusted by 50% based on the por tion of food consumed, For example, the dose for the size of the meal would be as follows: small (0%), regular (100°) large (1503). MDI should also incorporate supplemental insu lin to correct hyperglscemia. A comman method to caloalate the correction dose of insulin isto give an adlitional | unit of ‘ogular or arsilogue insulin at the time of the premeal meas Lbremen¢ for every glucose values maid. 2:8mmol) above the target glucose value In Insulin sensitive individuals and Insulin Type Onset Peak Duration Repid-ctng analogues Liprojaspatghlsine S-1Smn4550min 24h | | inalecinuin 515m Somin 23h | | ‘epaerteseel ase | ing enalagie | | tiproizcoumiy 55min 4590 24h | | shoracting } Human regular Osby) ashi adhe | Intecmadiat-aceng NPHineuin 13h 410h_ teh | Concenvatedhuman | requir | MumanreguerU500 05h © 25h 1B24h (s00uImo Long acting basal | snaleoues, Detemi 1th Nome zat | Gtoire 23h None? —20.28°h | begludec 13h None 22h Concentatedtseal mraiogue ula long-acting Gbrgine soouImL) 6h None 24d6h Deglidee(200U/n) 13h None 2442 Feemivedinsuins! 05th 1020 rin 1020 1020 min 1030 min 7086 NPHI30% rogue ‘TSSENPLI25% lsero 50% NPLSOR lspro TOENPAI3O%aspart om degluderi30% ene cine i mse pie “rosa mating minnie pat nme ‘tnd han lng pats catty ats ees na fo ws Cs {ral openers apd an shorting i 1 unit for every 25 myyall. (14 manoV/L in insulin resistant individuals. The supplemental insulin ean be given with the prandisl insulin in one injection, For example, an acditional 2 sanitsof insulin woul be given with the pratial insulin ithe ‘angel glucose was 120 mg/dl. (67 mmol/L) and the current ahtcose was250 mg/dl. 15.0 mmol/L) in someone with type t diabetes "Disorders of Glucose Metabolicm Premixed insulin formulations combine intermediate cing of long aeting basal insulin and rapid acting or stort desig insaimin ised concentrations These formulations ave ‘ypically administered twice dally and should pe consiaered for those who are upable or unwiling to perform mre fe {quent dally insalin inctions, Premised formulations can increase glicemic excursions inching hypogeern thisis a nonphysioigge regimen Inhaled inulin B aropi acting formation for prandiat ising, Te aviabiity of inated inslin in cartridges with preset doses of insulin (2, 8,ael 2st) mits the Mexiity Of insulin dosing. Pulnionary funeton should be assessed at beselne andl monitored because lang function may deine ‘with use of ale nsain sit provides continuous dcvery of basal frsulin and tesa bolus ealeulator programmed t achieve individ gy eric goals to caleulteprandial and bolus correction doses ‘The Endocrine Sockty rccoramends CSIL over MDI for al nul with type abet who ave no attained thelr ew? ‘loin A, goal and for thos: who have attained their A, al thu have lange glycemic variability, severe hypogtyeemia o¢ ‘hypoglyemia unawareness. Additional considerations include srneed for lexi in insulin delivers early morning hyper giyceriz (dawn phenomenon’) active syle, oF paient reference. Tere ae CSIl systems that will decrease oF top “elivery oftsulinifalacose levels fal below a threshold vaae that fs Set within the CSM aster and wil increase delivery slucose eels are above a threshold value tn delety il be seintated or inerese decrease back to baseline when the threshold is no longer met Hiypouycemvia and weight gain are ssh associated with inaalin vee The risk of hypoglycemia ower with analogue rst compared with regular insulin due toa shorter re tion of action Hypoglycemia caused by nsullnstacking occu ‘when insulin dosing Stoo frequent and overlaps wilh the duration of action of a prio inulin injection, This can be avwided by allowing ol Kast 3 10 4 hous between sequential injections of analyse scl, ‘An adjunctive therapy approved for use with insinn «wpe dlabetesispramiintde, an amylin analogue Praline fan lead to improve glycemic contol, decreased insulin Gloss, el eght loss through delayed gastric emptying imnenease sity and decreased slucagon secretion. A + Life long insalin therapy is required for persons with type 1 diabetes methtus. «+ ‘The Endocrine Sneiety recommends continuous sub culaneous insulin infusions over multiple daily doses ‘of insulin forall adalis with type T diabetes who have ‘ol attained their hemoglobin A, goal and for those ‘who have attained theit A, goal but have large slyee mie variability, severe hyposlyeemia, or hypoglycemia 12 Therapy for Type 2 Diabetes Mellitus As beta cell function declines, phacmacologee theraptes must ‘often be combined with iestyle modifications toobiain glvre mic control Therapeutle options may include monotherapy oF ‘combination of eral agents with injectable agents (Fable 10). the ADA recommends initiation of monotherapy if the A i less than 8% atthe time of iagnos's, Metformin is the recormmended first line oral agent for newly diagnosed type 2 dliabetes due to known effeetiveness and low hypoglycemia sk. Gastrointestinal slde effects of metiorinin are common and may be reduced by shoe titration of doses, aeministration ith foud, andor use of an extended mlease formulation. Lacie acidosis Is & rate, potential risk associated with met formin use, Heart failure requiring pharmacologic treatment and hepatic dysfunetion may inerease the risk, Am estimated slomerular filtration rate (@GER) greater than 45. sml/min’ 1.73 m? is recommended for metformin faitlation to avoit potential lactic acidosis with kidney dysfunction. Clinicians, should assess benefits: and risks of continutng therapy ia patients whose eGER falls below 45 mLomnin/1.73 mn! during therapy: Metformin fs contraindicated at «GER tess than 80 mL/min/4.73 mv’ I an feelinated contrast agent is administered with an GER between a0 and 60 ral vin’ 1.78 m, metformin should be held until kidney function isstable for hours. Metformin should also be hell insitations that may induce dehdralion, suchas vornitingor diarrhea, \ reduction in vitamin Bites tinal absorplion occurs in up to 30% of patients on metiormit Whereas §% 0 10% develop vitamin Fi, deficiency. Perindic monitoring may be warranted, particularly in the setting of snetnia or peripheral neanoathy. ivcemie control should he assessed every 3 months with adjustments therapy’ unt the glycemic target is achleved, and every 6 months if at soul. There are limited data on co parative elcetivenesstoguide thesdition of additional agents wien glycemic goals are not met wit anetiiormin and lifestyle rmodifiations: thus, many guidelines are based on expert ‘pinion. if the hemoglobin A, levels 0% or higher atthe time Of diagnosis or after 3 months oF metformin therapy the ADA dvancing to dual therapy defined as metformin ‘combined wilh another therepeutic agent (sxe Table 9 and Table 10), For individuals sth CVD, therapedtie agents that have heen shown! to reduce major adverse cardiovascular events (canagliflorin, empagtiNazin, and lirgglate) and ear diovascular mortality lempaglifioain and Hiraghuttde) should be considered for dual therapy AACKACE recommends initia Hon of metformin ifthe hemoglobin A, level i less than 75% at diagnosis, ‘ual therapy should he iniffated if the hemoglobin A,, level 67.5% OF higher at diagnosis or afer I months of mono therapy. The ADA and AXCE/ACK both recommend advance ‘ment to triple therepy if dual therapy fails to meet glycemic souls after 3 niontis, Triple therapy shoul be advanced 10 combination injectable therapy if glycemic gpals are sti recommendsDisorders of Glucose Matabalicm Class ‘Mechanism of Acton Disacvantages Long-Term Stucies on Definitive Oxteomes resin Deceaseshepaicglucose Increase Hypoahcemia, weight aan, Deceasinmerevascar production traning equrea, injectable evonstUCPOSF= SSrme pulmonary onc Incioahe pereral aloe Sree ON, ioe Suppresses ketogenesi Suffonpiros Suimubtesinauin seccton —Irereaoo—_Hypagheemialespecilyin _Detresreinicronasculo iobbuomise GNgewiilonghalliveser_ evens UKPDS) poste chorproparde Toc pODICTORE Et! memeeth OOD Gone Goce ayeace gasleclsglecnsedonecn shloisglinoptide Srcbiy Biguenides(meterin) Deceaseshepaicglicoss Neural Dianhesandabdorind __Deceasa in CVD events sredhuion decomion viamin cuReosy we Glucosidase inhibitors iacarbose,mgital Thiazoldinediones rosiglitazone, plegltarone) Meghtinidee iepealnite, nateglivide} Anyin mimetic ipramirtide) GLP 1 rocoptoragoriets (excnatide nono oetondedreleace, ireghitide albigltide, inxconatida, dubalurde, sereahtidal DPP-4 inhibitors (siaaiptin,saxaatptn, linagiptin alogiptin Incteazesinsuin madhatad Uptake of glucose in muscles Inhibits polysaccharide Nowtral absorption Incieases peripheral uptake Increase of glucose Stimulster inulin valexes ——_Incraseo Slowsgestic emplying Deciesse Suppressor glucagon Incseases satiety Glucors dependent ineraate culkin aecration Sloorsgestic emptying Glucose dependent Increases stiay Glucosedependentincesse Neutral in insulir secretion Giuceae dependent suppression of glucagon eficiencyiactc acidosis (core) Contiaindicared with progressive ver ney, or fardlacfalure Fltulonce abdominal ecco Fluid erercion,heactfallure, edama fractures, posible Increased stot Daceer acer with pioglitazone Hypoalycoma, weight grin, reguert dosing Nausea, vomiting, exacerbates gastroparesis, inereased nypogheems rsk lwih concamtantuse o! Insull, raining requred, injecratte,requert sesing Hypcalycerniawhanusadin orbemtonwah ufonylareae, nutes, vomiting, darrhes, ‘xacerbatee gastroparesi«: ctead tert aie poesia pancrestts, animal studies demonstrate C-cal hyperplacia ond madulary thyeotd tumor raining fequred, injectable Hypoglycemia when usedin cembinabanweh sulfonylurea, increased rok Ofinacsons, possible increased risk of pancreatitis, dermatologic reactions, requires dose acustments fordecreasing ichey Runcvon excepttor Tinagiptin Possible decrease in CVD fevents in prectes (GTOPNDOMY fos decraton CVO en onnpog uae Proncivel | | Nee | None | Decreases in CVD avente and mortally high isk dkidualewthiyes 2 diabetes with raghtide (EADER)? nceased heartfailne hosptalastons[saxagliptin (AVORTIMISIF (Cominves on he next page) 3Disorders of Glucose Metaboliem Long-Term Studies on Definitive Outcomes GLa Hhibiow lncresseslidhey ecetono’ Decteave — Fypocycemiswthinauln Decrease inCYDeverts (conegifoei, glucose sectetagogues, dehycration/ and mortality high-nsk Sapogiilorn hypotension, acutekidney indiiduals win ype 2 | petites inj (anagiftoan, Gabeteswith empagiticzin | ‘pagifiozn), (EWPAREG OUTCOME) hypersensivvly reactions, inereared candida nfectons andrinaty Yack nfacions “euglycemic” DKA, posse increase n aryptaatione (Gireglito2n) hyperialemia Dicressesincidentor ‘woreoring raphrapathy in high CVD rae nei wthtype? diabetos (EMPAREG OUTCOME) (aragiiben) acres DeceaseinCYDevertsin {carodioen) bloser iighsk nda wth Since copagiionn) ‘ype 2 diabetes wih anagiiezn(CANVAS Progen} | Bile acidsequestants eompletelyurdersiood: Newtal Coratipation dyapepein, | (colesevelam) ireraatod igyeride, | rose dacaoein nic ee ajcese procuction Sbeorption of ther Zossibeinewease inert rrecicatone ernie | Qe asa nets nsainsenstiy Newsol_Naseaothosiis fave Feb degene inc biomosnpuncqulek Ayn sepetnnne events(Creoset sate) | elsave) Seareats tral? | | [Si ai tea ON saa i BP oer ppt GIP ra le pr tr ghee cap ests Line output fappreamaely SOL} Asq1um porasstrnis-3.3 mEoy (Gammel), domes star Foul durinstenlghel [potassium chose, 20-30 mE, Brough a cenralline catheter Until the serum potossan level ig23.3esFefl 3 aml) “Then add 20.20 me of potassium chloride toeech iter EV fluids ta hep the serum. potassium levels the 4.0 50 | MEG/L (4.05.0 mmol} range. IF pH 66,9, consider sodium bicarbonate, 109 malin 400 maf waxer ane potassium chlonde 20 mEg, nfsed over Phoure lips €:9 orgmmer donot ai sori Geant: ae lap squm psn | Fypoiye resolved in DKA 25.2 mEg/L(5.2 mmo, do ane seo omcnonce, ‘re pusna qucorosradane: feraecrmm siete Cisse Weta areamat | acne hepa ee is alert and the hyperosmolar ® — ain eo ecamerons om ink A Umpire GE Mine IM Fiber yor Chronic Complications of Diabetes Mellitus Cardiovascular Morbidity A major canse of morbidity and mortality in persons with “diabetes mellitus fs cardiowascalar disease (CVD), Diabetes is an independent risk factor for CVD. Other significant risk fae tors for CVD include hypertenston, dyslipidemia, tobacco mse, family story, ane lbunuinutia, Simtianeous management OfCVD risk factorsisrecommended to decrease morbidity and mortality. Screening interval liste! abe 44 Hypertension contributes to the development of American Diabetes Association (ADA) defines yperten sion as sustained blood pressures 140/90 mm Ii or higher. Ching concerns for increased treatment compli cations with a Tower blood pressure target below 139/80 mm Hig, the ADA treatment goal for most persons 1s below 110/90 mm Hg. Those persons at high risk for CVD may alm for Tower blood pressure targets if this can be achieved safely. In contras.. guidelines from the American Association of Endocrinologists/Ameriean College of Hndocrinology (AACE?ACE) and the American College of Cardiology American Heart Association (ACL AMIA) and nine other organizations advocate for a treat nent target below 130/80 mm fg, for most patients with diabetes. ADA recommended! treatment strategies inelude idelines for risk factors are and microvascular complications. ‘The 20 lifestyle modifications (for blood pressure >120/80 mim Hg) and pharmacologic therapies (for blood pressure 2149/90 sn ig). Initial recommended antihyperte rewimens include ACE Inhibitors, anglotensin recepior blockers (ARBs), dihydropyridine caleium channe! block: ersvand thiazide diuretics, Multiple agents are frequently requised to reach the blood pressure target, Underlying, comorbidities: should guide seleciion of therapeutic ents, such as the use of an ACE inhibitor or ARR in the presence of microalbuminuria Lipid management in diabeles frequently requires combination of lifestyle modifications and pharmacologic agents, The ACC/AHA risk calculator can determine the 10 year atherosclerotic cardiovascular disease (ASC) tisk to guide therapeutic management, Statin therapy isthe ec ‘ommended intial pharmacologietreatmeny forall qualifying persons with diabetes (see MKSAP 18 General intemal Medicine) Antiplatelet therapy with aspirin (75-162 mg/day) ts recommended by the ADA for secondary prevention in those persons with diabetes anid ASCVD. Aspirin therapy for primary prevention af ASCY1) In persons with type 1 and type 2 diabetes may not provide universal henelit, so aspirin therapy (75 162 mgidiy) may be considered in persons, 50 years of ageandokder with at least one additional ASCVD risk factor. The ADA does not recommend aspirin therapy for persons younger than 50 years of age at low risk for aso.‘Chronic Clinical Situation When to Start Screening Preferred Screening Test Complication Screoning Frequency Retinopathy Type diabetes AtSyewrsater Annual Disted and comprehensive eye axarrinaticn® agnosis Type 2dlabotes —Atdiagnasia Annual? Dibted and comprehensive eyeenamination? Inpregnant Fisttrimester Everyvimesterard Dibted and comprehensive eye examination? women with ether thencloselyfor! type o! diabetes yearpestoartum Inwormenwith During Seme as Dated and comprehensive eye amination’ ether ype of preconception recommendatiors dabetesclanning planning (er eregnare Conception ocobrs Nephropathy Type diabetes AtSyearsafter Annually Albumin- creatinine ratio cn rane diagnosis spatiirine, GFR Type2diabetes —Atdlagnosis.—Annuaty= ‘lbumin-creatinine ratio cn ranclom spoturine eGFR Neuropathy Type tdiabetes AS yearsafer Annual ‘Skin sseesement evant for font feria louse Gistl symmmetic. diagnose auremitypuloe aasostment auralogi aceetsment polmeutopathy)® [iC-gmonofiamert plus 128-Ho turing fore salle ‘efeues pinpic,ertermperatire) TypeZalabetes —Atalagnotis Annually ‘Skin assessment evaluate for foot deters lower ‘xremiy pulse sesostment neurologic assessment (1t-gmonofiament plus 128-Hztuning fork ankle ‘eflees pinpick temperature) Cariovarcular Hypertension Atdingnosis ——Evony ist Blood pressure mescurerient dence Dysipidema Atdiagnosisand Annually ipid profile pprocto ntiting Buatio therapy cE cans gor "fool choogapty ew poabiea revi ls nel cpr theipeiciteenions nh cnn nti snahaugh dabece commonly ze eel sopty cher feral agra a hyped orl dus main) an chemoetrpcn xcs te heed nasopes 20ieaiigplisnostea PD 29220080 orth Anencansouston of Cnctenlocielogst and Amen College ot nanesnacag onthe cenprehrsvclye cabeses management ign 11 omen sary nora TBAT 12 A S83) | ‘= The American Diabetes Association (ADA) recommends ‘+ Liptd management im diabetes frequently requires a a blood pressure treatment goal helow 140/90 mm Fig combination of lifestyle modifications and pharmaco ‘or lower for persons at high risk for CUD ifthis.can be logic agents statin therapy is the recommended initial achieved safely; the American Assoctation of Clinical pharmacologle treatment forall qualifying persons with Endocrinologists/American College of Endocrinology diabetes. (AACEACE) and the American College af Cardiology! The Ametican Diabetes Associition (ADA) doesnot HVE ‘American Heart Association (ACC/AHA) and nine other ‘econmenciesaiat iment pencns pounger than. ‘organizations recommend a target below 130/80 mm 50 yeark of age at Sow reldfor athemeclerotic ig formost patients with diabetes, cardiovascular disease, (Continued) 2Disorders of Glucose Metabolism Diabetic Retinopathy Retinopathy is the leading cause of preventable blindness among persons with diabetes between 20 anil 74 years of age in developed countries. Risk factors for retinopathy include \duration of ciabetes, degree of hyperglycemia, hypertension, albnminris, and dystipidern Diabetic retinopathy changesare dlassified as nonpro |iferative (oceurs within the retina} or proliferative (occurs, in the vitreous or retinal inner surface), Nonproliferative retinopathy findings may include microsncurysms, dot and blot hemorrhages, hard exudates (ipid deposition), soft exudates or coiton-wool spots (ischemic superficial nerve fibers), venous bleeding, and intrarctinal microvas cular abnormalities. Neowascularization due to chronic, ischemia characterizes proliferative retinopathy. which may cause introcular hemorthage, cetinal detachment, and viston loss, Macular edema may occur with nonproiferative and pro liferative retinopathy. Screening guidelines were developed for early detection of asymptomatic abnormalities to allow for treatment inter ventions to prevent vision loss (see Table 11). Optimal contro! of blood pressure, glucose, and lipid parameters can prevent and delay the progression of retin ‘oputhy. Panretinal laser photocoagulation can treat high sk proliferative diabetic retinopathy and severe nonprolifera tive retinopathy. In addition, intravitreal injections with, anti vaseular endothelial growth factor (anti VEGF) to reduce vision loss associated with proliferative retinopathy, is not inferior to panretinal laser photocoagulation. Retinopathy may develop or accelerate during pregnancy oF with rapid glycemic improvements, and may require laser photocoagulation 9 decrease the risk of vision loss. Macular edema is preferentially treated with anti-V Intravitreal injections to improve vision loss, AnU-VEGF injections require monthly injections for at least 2 months followed by intermittent injections to prevent recurrent ‘macular edema. “Patients with type 2 diabetes should havean eye exami naton atthe ume of dlagnasss ‘+ Optimal controt of glucose. blood pressure. andl lipid parumesers can prevent and delay the progression of retinopathy. + Panretinal laser photocoagulation or intravitreal inje= tions of anti-vascular enelothetial growth factor can treat high-risk proliferative diabetic retinopathy and severe nonproliferative retinopathy, Diabetic Nephropathy Diabetic nephropathy isthe leading cause of end. stage kid ney disease (ESKD). Diabetes is typically present for 5 to 22 0 years priorto the development of nephropathy. Individuals wiih a Mist degiee relative with ESKD due to diabetic rneparopathy have increased risk of progressing to ESKD. themselves Measurement of estimated glomerular fitration rate (cGFR) and sereening for the presence of microalbuminuria is recommended for early detection of kidney disease (see Table 14), Urinary albumin excretion can be determined from a random urine collection as an albumin creatinine ratio (UACR). An elevated UACR level [220 mg/g creatinine) should be confirmed by multiple measurements over 3.10 ‘6 months due to possible temporary elevations from biologi cal variability. illness, hyperglycemia. heart failure, hyper tension, exercise, and menstruation, Annual measurements of eGFRand UACR may identity progression of nephropathy and guide therapeutic decisions. More frequent assessments. ray be necessary with worsening kidney function. An eGFR less than 30. mL/min/1.73 m? warrants a referral to a nephmlogist Uncontrolled hyperglycemia and hypertension are risk factors for diabetic nephropathy: thus treatment to attain plucose and blood pressure goals is recommended. The ADA recommends an ACE inhibitor or an angiotensin receptor Dloeker (ARB) as firsi-line therapy to slow progression of nephropathy and prevent CVD in nonpregnant persons with diabetes, hypertension, a reduced ¢GER {<60 mLimin) 173 nr), and an elevated UACK (2300 mgig ereatinine). An ACE inhibitor or an ARB isalso recommended for treatment fof an clevated UACH between 90 and 209 mgig creatinine in nonpregnant persons with hypertension, Treatment with an ACE inhibitor or ARB is not recommencled for patients with diahefes who havea normal blood presstce,a UACR level less than 30 mgig creatinine, and an eGFR level greater than 60 mLmin/1.73 m*. O REGPROWTSiE LS ‘+ Measurement of estimated glomerular Meration rate and screening for the presence of microalbuminuria are recommenced for early detection of kidney disease. *# The American Diabetes Ascoctation recommends an ACE Inhibitor or an anglotensin receptor blocker as first-line therapy to slow progression of nephropathy and prevent cardiqvasealar disease in nonpregnant per sons with diabetes, ypertension, a reduced estimated glomerular ftration rate (<60 mL/min/1.73 m, and an ‘elevated tring albumin creatinine ratio (200 mes, creatine), ‘ Treatment with an ACE inhibitor or angiotensin receptor blocker is not recommended for patients with diabetes ‘who have anormal blood pressure, aurine albumin-to- creatinine ratio level less than 20 mga ereatinine, and ‘an estimated glomeralar filtration rate level greater than 60 mLmin/1.73 m2,Diabetic Neuropathy SE? Diabetic nenropatly involves damage wo nervesor nerve roots due to hyperglycemia. Symptoms are dependent on the affected nervels) and may be focal or diffuse in nature, ‘Neuropathy may occur peripherally and/or affect the auro- ‘nome nervous system Glycemic contro! may prevent periph feral neuropathy and cardiae autenomic neuropatlyy in Individuals with type 1 diabetes and can delay progression of neuropathy in type 2diabetes. Diabetic peripheral neuropathy (distal symmetric poly ‘newopathy) typically nas an ascending presentation with 3 “Siocking and glove" distribution. It may involve damage to both small and large nerve fibers. Symptoms from small nerve fiber damage include pain, burning, and tingling. Small nerve flber abnormalities ea be deiected em examina ‘fon by assessment of pinpriek and temperature sensations, Abnormalities tn position sense, vibration, and light touch are indicative of lange nerve fiber damave and convey an increased risk for foot ulcerations, Assessment of large nerve fiber damage can be achieved by assessing ankle reflexes and with a 128-Hy toning fork and a 10-¢ monofilament. Since Giabetic peripheral neuropathy may be asymptomatic, sercening should vecur for early detection to prevent limb loss (see Table 14), Autonomic neuropathy may affect ene or multipleorgans ‘withsymptomss varying bascd on theaffected organ. Symproms, may include hypoglycemia unawareness, gastroparesis, con stipation, dlarthea, erectile dysfunction, and bladder dysfunc tion. Symptoms from cardiae autonomic dysfunction may Inclide orthostatie hypotension, resting siaus tachyeardia, and exercise intolerance. Cardiac autonomic neuropathy tan Iniependent risk factor for sucden death. ‘The goal of treatment of diabetic neuropathy is symp tom control. Two FDA-approved medications, pregabalin or daloxetine, are recommended as initial therapy. Other agents may provide symptom relief but are not EDA, approved and Include tricycle antidepressants, venlatox ine, carbamazepine. capsaicin. and gabapentin, The pri ‘mary treatment of orthostatie hypotension Is nonpharma ccologie and inchudes diet, use of compression stockings, and changing positions slowly. Medications that cause or worsen the orthostatic changes should be discontinued and other agents (lludrocortisone, midodrine, or droxt dopa) added for refractory symptoms, Small and frequent low-fat, low fiber meals may improve symptoms of gastro paresis. Metoclopramide is the only prokinetic agent approved by the EDA for the treatment of gastroparesis, Given the risk of sie effects, including, dystoni assessment of risks and benefits should be undertaken before prescribing (see MKSAP 18 Gastroenterology and Hepatology) Diabetic amyotrophy is a rare condition affecting the Iumbosaeral plecus thal may oxcur secondary to infaretion oF Immune vasculopathy, Presentation 1s acute and associated, swith severe asymmetric pain or preximal weakness in a lee swith associated muscle wasting. Partial remission may occu ‘ger many months, Treatment is supportive. Mononearopathies and nerve compression syndromes (carpal tannel syndrome, peroneal palsy} ean occur in patients ‘with diabetes. Mononeuropathies Frequently resolve without intervention within a few months. Compression syndromes ‘may respond to conservative menegement, or surgery may be ecessafy for symptom relief ‘+ Diabetic peripheral nearopathy (distal symmetric polyneuropathy) presents with a “stocking and glove™ distribution, involving damage to both small and large nerve fibers; symptoms include pain, burning, and Ungling. * Glycemic control ean delay progression of nesropathy in type2 diabetes, Diabetic Foot Ulcers ‘Significant morbidity and mortality areassociated with lower extremity uleess and amputations (see MKSAP 18 Infectious Disease). Lower extremities should be mspected at every vist anda comprehensive foot ecamination, including 10- mono {lament testing, should be performed at least annuclly. Risk, factors for wleer include: hypergiycemta, peripheral artery disease, history of foot ulcer or amputation, foot deformity peripheral neuropathy, impaired vision, tobaceo use, and dia ‘etic nephropathy. Yascular assessment should oceur tn per sons with absent pedal pulses or symptoms concerning for claudication. Foot care specialists should be involved in the ‘care of high-risk individuals. Puttents should be educated om the importance of daily foot inspections and properly fitting foonwear Hypoglycemia ‘Hypoglycemia is defined asa glucose value less than 70 mg/dl. (2.8mm 1, Ghcosevaus ess than 54 mg (8.0 mmol) ae srious and chnicaly significant Sry glucose yale at which a pemonreqaies exter ass ‘Srea tocorrettbe ius Tipe yepnrs Greincs: inh, aa, tachycardia are the normal physilogi esporse othe devel Gone ef brocinenis Cocnereaiiary barnes Guckeat crac excesiate exten wal orth hormone) ar: subsequently released by the body to correct hypoglycemia. Neurogiycopenic signs (altered mental status, jean, ordeal ies sees peace mia, Obtundation, seizes, and death may occur if Severe hypoglycemia is not corrected rapidly sere hypoglycemia is Hypoglycemia in Patients with Diabetes Mellitus Pr] Alypoglyemia can become 2 rate-limiting step in eemleguals for many persons. sieving. ay yere sequent hypoglyectnla 23Disorders of Glucote Metabolism (Ey Sees th sites coi defcts and can Tea wo dementia. Therapies must be adjusted to eliminate hypoghiee mia, and glyceraic goals should be individualized toraccomni ‘date targets that cin besafely achieved, Several factors contribute to hypoglycemia inelucling a mismatch of food consumption and insulin delivery increased physical exertion, weight loss, worsening kid ney impairment, abnormalities in gastrointestinal moth ity and absorption, and accidental intentional overdose of insulin, Older adults are also at an increased risk for hypoglycemia, Typoglyeemia ea also occur with the use of ora) aati diabetic agents due to incorrect dosages, drug: drag intemie tons, and intercurrent illnesses that alter the metals or excretion of dru, Lypoglycemia treatment inan alert person includes eon ssimplion of 15 to 20 grams of a fast-aeting carbohydrate fol lowed by 4 self montiored blood ghtcose SMBG) measure ‘ment 15 {0 20 unlmutes later. I the glucose has nol improved, repeat treatment with 15 grams of earbohyarates should ecu. After glucose normalization 670 mg/dl. [3.9mamalL),a meal (oF smack shoul De consuumed fo avoid recurrent ypaaiyee ‘mia. Glucagon shoul be provided to those persons ask for developing clinically significant hypoglycemia (64 mpd, {3.0 mmor'L}) and used ineramusculatty by lose contacts i the person isnot able to safely consume carbohydrates to cor rect hypoglycemia, Relative bypuglvcernfa characterizes symptoms of hypo lycemia in the setting of plasma glucase values greater than 70 maid. (3.9 mmol/l). This may eeeur with a large, rapid decrease In glucose OF rapid: normalization of glucese with treatment intensification in an individual with prolonged plasm glucose valves obove'200mg/dl. (11.1 mmol/l). Rel iypogyeemfs can be prevented by avolding lange glyvemie excursionsand byslow correction of long standing hypersly cconsa togonl toallow s longer adjustment period, ED ittiihiiis oa * Hypogicemia is defined as 2 glucose value less than TOmgiAl (8.9 mmol) and sericus hypoglycemia as fess than 54 mg/dl. (3.0 mmol/L). + Initial treatment of hypoglycemia requires oral con- sumption of carbohydrates or administration of ghica gon witha goal of mcreasing the glucose to greater than 7O mil (3.9 mmol/l) ‘+ Relative Kypoglyeemia can be prevented by avoiding lange gbeemic excursions ard by slaw correction of Tong. standing hyperglycemia to goal to allow a longer adjustment period. Patients Without EE Hypestyceria Diabetes Mellitus Hypoglycemia withoat concomitant diabetes is uncom mon and warrants farther assesment. A bypogiycenia 24 evaluation should commence If the criteria for Whipple triad are mete neurogiveopenie symptoms, hypoglycemia, at or below 55 mg/dl. (3.1 mmol/L), and resolution of symptoms with glucose ingestion. Laboratory measure ment of glucose must confirm true hypoglycemia, as potnt of contact (POC) glucose values are not reliable in this scenario. Hypoglycemia In persons without diabetes may be aitributable « the following causes: drugs, aleohol, IMness, organ dysfunction [kidney or liver), hormonal deficiencies (adrenal insufficiency), malnutrition, and pancreatogenous insulinoma or noninsulinoma (endoge nous hyperinsulinenie hypoglycemia that is not caused by an insulinoma), Although there may be overlap in presentation. hypo islyeermia typically occurs In the fasting or in the postpran dial state. Diagnostic blood and urine studies should be obtained during a byposiveerie episode in which Whipple (riad has been demonstitted, Ia spontaneous episode ts ot witnessed, measures should he implemented fo reere ate circumstances that normally induce hypoglycemia (fasting or ingestion of a gypical meal thal causes an ept sod In that particttlar pation), Imaging studies for tumor localization should only occur after confirmation of endogenous hyperinsalinism from the dlaghostic blood and ine studies. £0 ‘+ Imaging studies for tumor localization should only. ‘occur affer confirmation of endogenous hyperinsulin- ism from the diagnostic blood and urine studies. Fasting Hypoglycemia A prolonged fast, up to 72 hours, should be initiated if the hypoglycemia typleally oceurs while fasting, Fie blood specimens are drawn simultaneously every § hours: glucose, C peptide, insulin, proinsulin, B-hydroxybutyrate. Insuwiin antibodies ané an oral hypo glycemic agent sercen should also be measured at the beginning of the fast. Blood specimen collection should, increase lo every 1 0 2 hours when the glucose measure ment Is less than 60 mg/dl. (3.3 mmol/L) Testing is complete when one of the following param eters fy met: plasma glvcuse 45 mgidl, 2.3 mmol/L) oF below with neurogiycopenia, or plasma ghicose less than 55 mg/dl. (3.1 mmol/L) if Whipple triad was documented previously. POC ulueose values and hypentarenergte symp toms shoitld not be used to determine the end of the fast. Blood specimens should he collected again at the end of the 7H hour time period if neither of the above erhiesta has been met, The interpretation of the diagnostic testing rests is found in Table 15. To decrease she cos of thls procedure, the plasma glucnse should be sent to the laboratory as son as possible. and fits less than 60 mpl. (22 mmol/l), the ether four bleod samplesshould be sent. Ice Disorders of Glucoze Metabolism Metabolites of Sulfonylureas or | Moglitinidos Thsstnomes | a 7 7 £ Negaive Negative Surrepttioususe 1 1 4 Negative Postve of sulonyureas ormegltrides Soiepuious ae t 4 ‘ a ieee, Soain a ‘asain % 1 1 ‘ Positive Negative aulommune hypoaticerni cea L J i t Negative Negative ‘Sympsnmachyoma targa gee Sng Tro ner se rompeampnst relat cece hypeabenma Werle nd. pepe nd pcinninweindeatrect enopenrt ned pron ‘dtymbuynte wl be eed inte sence fisain but elected i yoaahcenith ienotmedtadby inn ‘irre in obo sen wana enon prcretogerous ypoaeom cone epost oi by Nagai | wns pout er IGM or pete maybe preduebytunon adinduesWypooheemi by mutton He nnn eceptar ith ubrcuanincescea gee For fasting hypoglycemia, five blood specimens are drawn simultaneously every’6 hours: glucose, C-peptide, insulin, protasulia, B-hydroxybutyrate; to decrease the cost of this procedure, the plasma glucose should be sent to the laboratory 2s soon as possible, and {Fits less than 60 mg/cl. (3.3 mmol), the ether four blood samples tould be sent. Postprandial Hypoglycemia Postpranial hypoglycemia typteally occurs within § hours of the last meal, Altered gastrointestinal anatomy, as ocears ater Roux en Y gustric bypass sungery, is frequently the cause of the postprandial hypoglycemia, Meals consisting of simple carbohydrates (pancakes, syrup, juice) are frequently the cul pril, A mised meat test consisting of the types of food that normally inckice the hypoglycemia should be performed to determine the cause. Baseline laboratory studies including, glucose, C-peptide, insulin, and proinsulin should be obtained prior to meal consumption. These tess should be repeated ‘every 0 minutes for § hours. If neuroglyeopenia occurs, the {ests should be repeated prior to administration of carbo’ ddeutes. To decrease the cust of this procedure, the plasma gl ‘cose shouikd be sent to the laboratory as soon es possible, and itis less than o0 mg/Al. (3.3 mmMOV/L), Ue other thtee blDod samples should be sent. Screening should also ogeur for insulin antibodies and ‘oral hypoglycemic agents if symptomatic Typoglycemia ‘occurs, Iniespretationof the results is similar to these obtained. during fasting hypoglycemia (see Table 15). Treatment generally consists of sinall frequent tnixed meals with 4 halanee of protein, fa, and carbohydrates: KEG LO MERITS SE ‘= Forpostprandisl hypoglycemia, baseline laboratory HVC studies including glucose, C-peptide, insulin, and pro- insulin should be obtained prior to meal consumption: to decrease the cost ofthis procedure, the plasma glu ‘cose should be sent (o the laboratory a Soon as possi ble, andifit is less than 60 mg/él. (3:3 mmol/L), the ‘other three blood samples should be sent. Hypoglycemia Unawareness. oO LUypoglyeemia unawareness is characterized by insulficient release of counterregulatory hormones an@ an inadequate autonomi¢ response to hypoglycemia. Prior episodes of hhypoglyoemia increase the risk of developing hypoglycemia unaviareness. Treatment involves relaxation of glycemic tar gets and modifications of hypoglycemia inducing diabetes therapies to avoid continued hypoglycemia. Avoidance of hypoglycemia far several weeks may reverse hypoglycemia unawareness in some persons and result in the ream of adrenergic symptoms with glucose levels less than 70 mg/l {3.9 mmol/). A continuous glucose monitoring system may be beneficial in appropriate individuals to provide early letection of impending severe hypoglycemia for early inter 251s of the Pituitary Gland Disorders of the Pituitary Gland Hypothalamic and Pituitary Anatomy and Physiology The ptitary gad io ected tat cl tric pemctor the spheroid sims. The opttecnism lace siperor othe pituitary gland, andthe carotid arteries renter! (ue 2. The gland is cotopoved of antcor petaryladenohypo pts), which s grtlartssue, anc the pester ptatary sland (neurohyponhyss), whieh arses fom neural tissue. A i pore torular mes courecestee Hypthnatis to the anterior ptitary whereas the postenor iutary pnd consbts of nerve endings projected from neurons in the tuprooptc and pemverircular mace in the Hypothalamus. Bath the portal network and hypothalaale neurons tel from the hypothalamas tothe ptahary through te ptatary atl: The eat arteries promde ood w the pany though the hypoptysal arteries, an venous drainage ours by means of the petrosal sinuses to the jugular vein, Sista and inabiony homey erred Hts porta blood by the hypothalamus, regalate te anveror pr tay, and the posteroe pituitary hormones are svthestein ths hypothalamic aici and Ged ough neuen ine released by the posterior ptltary and The aneriorpititary secretes sx pittary hormones: Ineinizing hormone (LH), folie simulating hormone (PSI, adrenocortcotmpe hormone (ACTH). prolactin, thyroid stimulating horton (TSH), and growth hormone (G1, Gonadotropin releasing hormone (CARH) is released feo be typhi tn ples, wiach a inrn'comit the release of an FSH, and FSH reguate male and female ‘epmiection thing Stmmulaton ofthe prado i produce TEAOGETO ded etic ts el 25 stn GOT HGURE 2. Aca! URI) and aitl MRI ght showngSeptaty san follicles and spermatogenesis (see Reproductive Disorders) Corticotropin releasing hormone (CRH), produced in the dypodtalamus, stimulates the production of ACTH tn the prul tary, which then stimulates cortiso! production from the adre nal glands. Prohciin is synthesized in the lactotroph cells. Is synihesls and secretion is suppressed by hypothalamic dopa mine, Which traverses the pitukary stalk through the portal circulation, TSH is released in zespense to stimulation from, yrotpin-releasing hormone (TRH) produced in the hypo: thalamus, TSH binds to receptors on the thyroid, resulting in synihesis and secretion of thyroid hormone. GH release is regulated by (wo hypothalamic hormones, growelt hermone releasing hormone (GHR#), which stimulates GH release, and somatosiatin, which inhibits GH release The posterior pituitary gland secretesuxytoctn, necessary for parturition and lactation, and antidiuretic hormone (ADH), which maintains water balance ‘Table 16 iss the pituitary hormones and the tial evalu ation for suspected pituitary excess or deficiency of each hormone. Pituitary Abnormalities Incidentally Noted Pituitary Masses When a pituitary lesion i discovered incidentally on imaging obtained for an unrelated reason, the lesion s termed. “pitu tary incidentaloms,” Small incidentally noted pituttary lesions fare quite common. In patients undergoing MRI for nonpitut {ory reasons, microadenomas are found in 10% 10 38%, whereas incidental maeroadenomas are seen in (2%. Most pituitary incidentalomas are benign nonfunctional pituitary adenomas; however, a small percentage may be Rathke cleft sb, cruniopharyngiomas, or meningiomas. In patfents with history of malignancy, metastatic disease should be consid ered. Puultary adenomas measuring 1 cm or larger are (ta nd cart arr (caved eo) 26Disorders of the Pituitary Gland Pituitary Hormone Excess Pituitary Homene Peripheral Hormone Initial Testa) ACTH Cortical 2A Hour urine roe corseol( +2) OR nocturnal salvary cortizol(«2) OR overmightlow dora dexamethasone test ADH ADK Simutaneousse-um sodium, serum osmdlaliy, urine sodum,and vine osmelalty ou Ice se 13H Tryroxne, TSH, fre ce total) thyroxine iviodothyronine PRL Prolactin Serum prolacin ry Hormone Deficiency Pituitary Hormone Peripheral Hormone Initial Testis) Cenfirmatory Test™ ACTH Corts Simutaneous ACTH, cortical ‘ACTH stimulationtest ADH ADH Simulonoousserun sodium, urine undaeum esmoialiy Water deprition test Land FSH? Testosterone or Simulanecusll, FSH, total testosterone (male), estradiol festiaciol female) 1s Thyroxine, SirulancousTSH, fee (ortotal thyroxine triodothyronine oH IGF ora GHRHarcininetes Insuln tolerance test macrosdenomas; those measuring less than Lem are microad- enomas {see Evaluation of Pituitary Tumor) REGHOUNEaisieecceine eet + Most incidentally noted pitatary masses are benign nonfunctional pituitary adenomas; however, a small percentage may be Raihke cleft cysts, craniopharyngto ‘mas, or meningiomas. Empty Sell. Emply sella is also tvpieally an incidental finding on imag, done for a nonpituitary related reason, Iti « radiologic ind ing, rather than a medical condidon, This term is used when the sella turciea is enlarged and not entirely filed with pita tary tissue. No gland may be visualized, or itis inordinately small, Primary empty sella s the result of herniation ef subs rachnoid space into the sella, compressing the normal pitui tary gland. Primary empty sell ie cansed by incompetence of he sellar diaphragm, increased lauracrantal pressure, oF vO ‘metric changes in the pituitary gland (as can ogeur in preg nancy, particularly in rmulriparous women). Secondary empty sella can be related Infurction of a pltulwary winor or ether causes including infection, autoimmune disease, trauma, of radiotherapy Paticnts with an empty sella usually fave normal pituitary function because there is gland present, bat itis Lining the enlarged sell, like the rind of an orange. All patients with cemply sella should have elinial assessment for signsand symp, toms of pitutary deficiencies. Hyperprolactinemia, the most common pituitary abnormality in empty sella, can be treated ‘with dopamine agonist therapy when needed. Asymptomatic patients should be screened with 8 aut cortisol evel measure- ment, as wellas TSH and free T, measurement, Additional test ing should be targeted tothe pituitary ases if there are signs or symptoms of deficiency. Patients with no initial abnormalities are unlikely t0 ‘develop hormonal or radiologic changes. Because of the theo- retical sk of progression, however, 1s recommended that asymptomatic patients with empiy sella have repeat endo- vine, w radiologic, and ophthalmologic evaluation in ‘36 months. Iino progression, turtherevaluation can be limited to those who require it clinical MELO SS ‘+ Empty sella is dlagnesed when the sella wurcica is enlarged and not entirely filled with pituitary tissue all patients with erapty sella should have clinical assess ‘ment for signs and symptoms of pituitary deficiencies, 27Disorders of the Pituitary Gland Other Abnormalities The pituitary gland can also be affected by other pathologic messes, such as autoimmune disease infection, infiltrative diseases, metastatic disease, or infarction (Fable 17) Drug-Induced Abnormalities There are a number of drugs that can affect pituitary gland function. Any hormone administered exogenously provides newative feedback to the normal cells in the pituitary glare Exogenous estrogen or testosterone will suppress the gonado ‘rupins, LH and FSH, whereas excess exogenous thyroid hor ‘mone will Suppress TSH. Likewise, physiologic and supra physiologic doves of glucocorticoids will suppress ACTH. (Optates have a number of effects. Most notably, chromic opioid, luge suppresses gonadotroph funtion, resulting in hypogon adotropic hypogonadism, and is increasingly recegnized as a cause of ACTH deficteney. A relatively new class of drugs, checkpolnt-blocking anti bodies, hae been associated with pituitary abnormalities related (0 hypophysiis, These drugs, including nwvolumsb, ipilimumab, tremelimumab, and pembrolizumab. are used 10 treat metastatic melanoma, renal coll carcinoma, non. small, cell ung cancer, and hel and neck cancers. Hypophystiis ‘occurs in 0.5% t0 5% of patients anc often presents with bead ache and fitigne. Endcerine evaluation usually reveuls seccndary adrenal insufficiency (ACTH deficiency] and see ‘ondary hrypothyrotdism (TSiI deficiency), as wellas low levels, of LH1,GHL and prolactin. Imaging demonstrates enfiancerent andor enlargement ofthe pituitary gland with thickening of the pltutary stalk. Diabetes insipdus is uncommon. Treatment includes replacement of the hormone deficiencies along with high-dose glucocorticoids ty (reat the inflammatory process Despite resolution of the inflammation, hormone deficiencies often persist Mass Effects of Pituitary Tumors Mass effects of pituitary turnons most commanly include com. presion of the pitattary gland resulting in hormone deticien cies or compression of the optic chiasm most commonly resulting in bitemporal hemianopsia: other patterns of visial Joss can also oceur Stalk compression «an Kal to yperpco lactinemia, Headaches can be a symptom of pituitary tumors Ibat do not correlate well with tnmor size. Headache alone is nolan indication for surgery. Pituitary deficiencies related to compression ofthe gland ary from an isolated hormone deciency, most atten gonadotropin deficiency, to pankypopituitarism (deficiency of all anterior pituitary hormones). Similarly, pituitary tumors can have variable effects om compression of sarroundin ructures. A rapidly growing Pathology Cause Mass Effect Hormone Abnormalities Clinical Context Inflammation Lymphoaytic| ‘Autoimmune Mostcommon is ACTH Pregnancy, postpanura Liypephytis deficieney Metastasis of Opener imalignanttumer dysfunction occurs topituitay gland in 24% Canazohive ‘Ganialnene pasies ‘enc headache Fitter catcinoma (rare}0. ofa umer inal Malignantpiuitsry —Oftnprosent pituitary tumors eeeennond Disbotes insipidus most Patents with the following somnman ppammary malignancies: breast most commen) ang, Also can have anterior oe pituitary defies + Mestofionthare ieseme Patients foundtohove puta pitutay hypersscieton —_adanomawithsignifeant father tha deicincy ‘cavernous sinus invasion or xprosillar eaansion Infitrative Sarcodsis Pitutaryinftraton Possible Combirationofanteror Occurs inupto 10% of patient and posterior ptutay withsarcoidosss abnermaities Hemectromatosis __rondeposition No Gonedetiopin deficiency _HFEgene mutation Langerhans ell Depesition of No Diabetes inspicue Rorely occurinaduls hetogrosie Langerhore colle : fine the itty {es ky arteror otto lend icencies 28pituitary tamor or rapid expansion duc o pituitary apoplexy icudden hemorrhage ar infarction of a pituitary adenoma) causing compression of the optic chiasm may result in com plete bitemporal hemianopsia or even blindness. Pituitary apoplexy may even result in eranial nerve (CN) palkies off CNe IL, 1V, and Vi, whe pituitary tumor that abuts the optic chiasm may cause minimal or no loss in peripheral vision, All patients with pituitary tumors that abut for compress the uptic chiasma. should have a evaluation by an ophthalmologist (preferentially a neuro-ophthalmologis) Any abnormality on vistal examina surgery, tunless the ttmor isa prolactinoma. ED Pituilary tumors can invade the cavernous sinus but rarely cause mass effect on brain tissue or narrowing of the carotid within the cavernous sinus. * Mass effects of pituitary tumors most commonly incude compression ofthe pituitary gland resulting in hormone defictences or compression ofthe opticchasm most ‘commonly resulting in bitemporal hemianopsia: stake compression can lead to hyperprolactinemia. a slowly growin on is an indiention for Evaluation of Pituitary Tumors In patfents with 8 pituitary tumnor on CT imaging, a dedicated pituitary MBI with and without contrast with dynamic cuts, through the sella should be obtained. A formal visual fleld ‘examination is requiced for any tumor that abuts or cont presses the optic chiasm, Pituitary hypersecretion should be riled ont by measare ment of prolactin and insulin-like growth factor 1 (IGF). Evaluation for Cushing disease is not necessary in patients ‘without signs or symptoms of cortisol excess Pituitary tumors can also cause hypopituftarism, Screening for bypopituitarism is recommend in all pituitary tumors regardless of symptoms with measurement of FSH, LL, cortisol, TSH, free thyroxine (1,), and additionally total testosterone in men. Hypogonadotropic hypogonadism can be assessed in premenopansal women through menstrual hisiory. A history of oligomenorshea or amenorthea would raise con~ cem for hypogonadotropic hypogonadism and require further hormone testing, whereas a history of normal menses would cssentially rule out hypogonadotropie hypogonadism. Abnormal baseline testing may prompt further stimulatory ‘esting to confirm hypopituitarism (Table 18), and referral 10, an ersloctinologit is recommended. patient does not require surgical intervention for mass effect oF pitaitary hypersecrstion, repeat pitullary hormone. assessment and imaging is performed in 6 months for mac roadenomas and then yearly if no change. Microadenomas should be reassessed with imaging in L year and then every I (0 2 years thereafter. Repeat evaluation of pitutary function is not necessary in microaenomas if initial testing is normal and there has been no change clini cally or in the pitsitary MRI. Disorders of the Pituitary Gland After 3 years of imaging follow up for a pituitary tumor (both miercadenomas snd macroadenomss), imaging can be performed less frequently, as long as clinical status of the patient remains stable. ‘METLOLN SSS SUIS SRSA + Pituitary hypersecretion should be ruled out by meas urement of prolactin and insulin-like growth factor I ‘evaluation for Cushing disease is not necessary in patients without signs or symptoms of cortisol excess + A history of olizomenorthea or amenorrhea would raise ‘concern for hypogonadotrepic hypogonadism and ‘equi further hormone testing, whereas a history of normal menses would essentially rule out hyposonado- tropic hypogonadism. Treatment of Clinically Nonfunctioning Pituitary Tumors Patients with a nonfunctioning pituitary tumor should be referred for neurosurgical evaluation ifany of the following axe present: visual deficits related to the tumer, a lesion abuts or compresses the chiasm or optic nerves on pitsitary MRI, or pituitary apopleny with visual dstunbance, Surgery should aio be considered far a tarnor with clinicaly significant growth, suchas growth fowant the opti chasm and for patients with new loss of endocrine function. Wonnea with a maeroaderoma lose to the optic chasm who are planning pregnancy may benefit from surgical derompression ofthe pitilary tumor dae to the risk of enlargement during pregnancy. Microaenomas rely merease in size during pregnancy. Uhe mest common surgical approach for these tamorsstranssphenoidal through the nares or mouth, Oceasionall craniotomy is needed for very large tumors. Most nonfunctioning macroadenomas wilt have immunceytochemisiry consistent with 2 gonadotroph ‘adenoma and are cinicaly “silent” (without hyperseeretionof functional gonadotropins) + Patients with a nonfunetioning pituitary tumor should de referred for neurosurgical evaluation If there are vis, ual deficits related to the tumor, a lesion abuts or com ‘pressos the chiasm or optic nerves oa pituitary MRI, oF pitultary apopkxy with visual disturbance is present ‘+ Surgery should be considered for atamor with clint cally significant growth, such as growth potentially alfecting vision, and for patients with new loss of endoerine function. Pituitary Hormone Deficiency Fareed oe ee ee brid detetonies Remomarasaceadtcteanperadon of thendr trl plukary cells by a tumor o sa complition of rail Para nati A aT UGS ad cao 29 vcDisorders of the Pitui |Lladication Technique r ACTH(cortsol) cohciency ACTH stimulation test | on | N. | | 60 mnites. | ADH defciency — Waterdeprivation text, on followed by Hest iFindicated ehenesoes (ne coca eels? Pater halon 2% ef body ueshe rie cnlayt abe or2 we ae Pause s295 nOungh.0 Serum soun> 45 ef mel) carne sate nal ine relly $00 Oar, serumouolaly 9295 nOsaveg or Stenson Seat oral Si cies uaalecni | Deets cecleyeius eonriecy eee eee Gromh omone excess (Gcromegai) Glucose tolerance test $50 rites ‘Measure baseline serum corso level. Agministor 25039 of yrthoic ACTH IM ‘Measure corse! levels at 30 and, Patient emptesblader, and baseline weight a meaaured Measure urine volume and osmelalty hour Meacure serum sodium osmelality, and aoa eey2e The tstis stopped wlien one ofthe folowing occur: 75-gorel glucose tolerance test Measure glucose ard GH 310,30, €0,90, 120, ard Interpretation Serum cortisol level >1Byg/ol (496.8 rirol/L) at any measurementindicates normal resporse Woter deprivation tet interpretation: Une osmoialty >750-860 mOsmn/ka E.Gisa normal response to water deprivation indicate ADE production and peripheral effect are Intact Serum osmolalty>295 mOsnivkg HO andlorseruin socium +145, imq/L(145 mmol with inapproprictely cite ure (urine osmolaliy/plasma esracality <2) ia shagnoste of 0 Desmopressin challenge interpretation: | Urine osmolality »B00mOsn/kg afer desmopressinis consistent with ‘complete cenvval DL Noinciessetnurigecariolliny | (omaine 2300 mOsm edlognetic of compote nephragenieD. Urine osmoiaity beween 300ard 820mOsm s consistent with parval DI GHbe maintained in the mid to upper half of the nocmal range. While it takes 6to 8 weeks for TSH to accurately reflect thyroid aDisorders of the Pituitary Gland hormone status in primary hypothyroidism. free T, levels ean be checked 2 to 3 weeks after a dose change to assess for ade- quacy 1n secondary hypothytoidism. ira ‘+ Treatment of thyroid stimulating hormone deficiency is, chuily administration of levothyroxine; only fe thyrox- ine can be used to monitor dose adequacy, and free thy- roxine should be mainiained in the mid to-upper half of the normal range Gonadotropin Deficiency Gonadotropin deficiency can be a result of pituitary disease ora result of gonadotropin-releasing hormone (GnRH) deft céeney as is seen in Kallman syndrome and kypothatamic amenorrhea, Certain drags, including opiates, can also sup press GinRIl, Deficiency of gomadotropins, LK and FSH. results in deficiency of mate anc! female sex hormones. The combination of low or inappropriately normal LH and FSi with low sex steroids is termed “central” or “hypogonsdo. tropic” hypogonadism. Treatment of bypogoracotcopic hypogonadism ean uso ally he achieved by replacing sex sewids in those with no contraindication and who do not dese fertility; testosterone treatinent in men and combined estogen- progesterone teat iment in premenopausal women are used. While orl contra 10 em) to detect metastatic isorders of the Adrenal Glands disease or paragangliomas t detect multiple tumors. Fludeoxygluicose position emission tomography is more sensitive for detection of metastatic disease, but Its use is, generally reserved fbr those patients with established malig, napt tumiors The definitive treatment for pheochromocytoma!para yanglioma is surgical cesection, Preoperative B receptor blockade with phenosybenzamine for 10 10 1a days before surgery is essential (0 preven! hypertensive crises during, The dose is progressively increased to achiew a blood pressure oF 130/89 mum Hig oF less and pulse of 60 10, 7)/min seated, and systolic pressure of 40 mm Ig oF higher swith pulse of 70 to 80.aninstanuding Side effects inckade diz ines, nasal Congestion, andl fatigue, To facilitate dase exca lation and mitigate the volume contraction effects of a meepior blockade, patients are instructed to Hberalize their salt and fluid intake c- Dlockade is acheved to manage reflex tachycardia, but it Should never be started prior to adequ: A B blocker is added once ea blockade because unopposed a adienengie vasoconstriction can result ina hypertensive criss For large pheochromocytomas with a high hormone seeretion rate, otheragents such aya calcium channel blocker andior metyrasine are added t the treatment regimen. Calcium channel blockers can also be used in patients who develop significant hy, Selective 0: receptor blockers such as daxazesin can be used as.an alternative t phienoxshenzamineif availability oF lack of insurance covenige of the liter isa problem, Pestoperatively patients cen have sygnificant hypotension, an most require ‘uid and sion on small doses of a blocker cacopressor support at least briefly in the Adrenal Mass Overall MRI Sigal Intensity ‘Rdersladseona |) Dianetar aan Donsitsc1OHU bontenseonT.veightedimages hecanimsltethenconet'* Corea wach oSO%(O rin} Round dexrmeone ackenccotics| sel >em Density 10H ypu red rg! aaaeaied Heterogeneous enhancement? — Contrast washout <50% (10 min) iroguac nar Cai ac | Pheochomocioma Yorablesize Donsigys10HU Hypetnionseon T2weighted images | | iedeetee cee verte | | tntencomenbowiconss coe tomy | Tout dears | Con be bilateral Metatser Veviable marge Censiy>t0HU Vypeiitenseon 2~weighed imiges | Con be bilaerl Conca nadhou'<50% Orn | Siren come hs awwe orders of the Adrenal Glands postoperative period. Patients with pheochromocytoma i have Impatred fasting glucose or type 2 diabetes related insulin resistance induced by catecholamine excess. This can improve or reverse following adrenalectomy. Approximately 83% of pheochromocytomas’peragangiio ras are benign. Pathologie findings do not predict which ‘urnors will become malignant and develop metastases. Since metastases can occur decades after the initial diagnosis, patients should undergo long term annual biochemical sercening, typically with plasma free metanephrine. + Initial tests for pheoehwomocytoma include measure ‘ment of plasma free metanephrine levels or 24-hour ‘urine fractionated metanephirine and catecholamine levels; certain medications can ailect resuitsand need to be discontinued at least 2 weeks prior to testing ‘+ The search for a tumor should begin when a biochemical iagnesis of pheochromocytoma paraganglioma isclear {in laboratory zeal, ro avoid misdicgosing an incidental ‘onflunctioningadrenal mass 2s a pheochromocytoma, ‘+ ‘The definitive treatment for pheochromoeytomalpar ganglioma is surgical resection; preoperative «ac blockade with phenoxybenramine is essential 10 prevent hypertensive crises during surgery {Selective oc 1 receptor blockers suchas doxzzosin can be ‘used as an alternative to phenoxybenzamine if availability ‘or lack of insurancs coverage ofthe later Isa problem, Androgon-Producing Adrenal Tumors Androgen-producing adrenal tumors ate rare and lead 10 snenstrialiegulasities and virilzation in women including hirsutiam, voice despening increased musele mass increased libido, and clitomomegaly. Tumors secrete DHEA/DHEAS and anirostenedione. which ae subsequently corwerted io esos- terone in the periphery. DHEAS seereting tamors of the adre nal gland are realy visible on CT imaging, an adrenal vein sampling'0 oealizethe tamorisrarel requires. Apprcximately 50% are beniga, andthe treatment of ehoies is section Adrenal Hormone Deficiency Primary Adrenal insufficiency Causes and Clinical Features Primary aac insulTickeney (Ais 2 life threatening disor der that often presents with insicious onset of symptoms making diagnosis achallenge (able 28). It may sso present as adrenal crisis, olten precipitated by an acute illness or the initiation of thyroid hormone replacement in a patent with unrecognized chronic Al, Although skin hypenizmentation from stimulation of melanocytes by high ACTH leves is con sidered hallmark of primary adrenal insuicency, tis not present in approximately $i patients. The most common cause of primary adrenal nsulliciency is autoimmune dsteus tion of all layers ofthe adrenal cortex leading to progressive smineralocorticoid, glucocorticoid, and adrenal androgen dei- cienes: Most patients have postive 2 lylrospese antibodies, and approximately 90% will develop another antormmune Hormone Deficiency Signs Corisol Fatigue Hyperpiomentation® (palmar creases, extensor Hone ity surfaces, buccal mucosa) eee Deceasein a ‘weightloss Anorexia Nauseaivomiting [Abdominal pin Artvalgia Myla Aldosterone Sateraving Onhostasis Dizziness Hypotension Hea. Reduced libido Decreased axltary or pubichair Laboratory Findings 4Serum cortisol ‘Plasma ACTH LSeum sodium Plasma glucose! TPRA, sD Serweranclaen T'Serum potassium Serum DHEAS “nc. “con an ipoendocrine disorder in their ifetime (primary kypothyroidism, primary ovarian insufficiency, eelixe disease, hypoparathy ridism, or type 1 diabetes mellitus), Primary adrenal insullicieney can also be caused by infil trative Gisordens such ac infection (tubereulosis, fungal infec tions), sarcoidosis, and lymphoma, whieh result in bilateral adrenal gland enlargement. Metastatic disease involving the adrenals, mast commonly fram hung eance, renal cell eares oma, and melanoma rarely leads to axtrenal insuliciency ‘even i both adrenal glands an’ involved Bilateral adrenal hemorrhage can present as seute adrenal insufficiency and should be considered if unexpected hypo Tension develops, Risk factorsfor bilateral adrenal hemorrhage include protein € deficiency. anticoagulation, Intrasaseular coagulopathy. and sepsis iseminated Diagnosis An algorithm for the diagnosis of adrenal insufficiency is out ined mn Figure 5, Initial evaluation inciudes the measarertent of ‘oming serum total cortisl and ACTH levels. Primary adrenal insufficiency is confirmed by the combination of low serum cortisol and elevated serum ACTH levels, Important considers ‘Hors in the interpretation of the results are shown in Figure 5 and often require referral to an endocrinologist, Additional valuation may include measurement of 21-hydroxylase anti- bodies: positive 21-hydroxylase antibodies are found in approximately 90% of autoimmune adrenalits cases. nega Live, CT scan of the adrenal glands should be obtained, Disorders of the Adrenal Glands ‘Treatment Both glucocorticoid ang mineralocorticold therapy ts required {or treatment of primary A\. The preferred glucocorticuid is, hytirocortisone taken 2 or’ times dail: Adherence to multiple daily doses can be challenging so prednisone can be used! asan, altemative (Table 30). The principle of replacement is to administer a higher dose in the moming and to avoid replace ‘ment in the evening. Despite this attempt to mimie diurnal variation, patients with primary AT report decrease in health related quality oft. 1 imperative to avoid overreplacement with glucocorticoid, to avid iatrogenic Cushing syndiome with its isk of obesity type 2 diabetes mellitus, hypertension, hyperlipidemia, hone loss, and exrdiovaselar disease. Some patients “feel beiter” at higher than physiologle replacement doses, bur the risks outweigh the benefits of supraphysiologic doses. Minerajocortico‘d replacement is achieved with daily Avdrocortisone. DHEAS replacement is controversial in ‘women due to lack of robust data for benefit and eoncems, regarding the safety and quality of US. preparations, which are supplementsard not regulated as drugs, Patients cannot mount an appropriate inerease in cortisol with illness, ang therefore, instruction in *sick day” mules is essential o prevent adrenel crisis (Table 31), Tor minor physt aloe stress states such as respiratory infection, fever, or minor surgery under local anesthesia, patients should doable or triple their baseline glneoconicoid dose for 2 t0 3 days, Higher doses uf glucocorticoid are required during moderate ‘or major phiysiologie stress. Patents who present with adrenal Exclude conditions that ator binding slobutns orl acvogen, low Be aware of cent ar cumort slucsearticd woe (al inksled topical, nt ote eee —— ——— Conisol>i5yolat | Consol 245 pala. Conical <3 pla ACTH stimulation test Adria 250 meq ACTH Measure cortisol 9G 30, ane 60 minutes Ercees adrenal Peakcortsol Peakcousa Arenal Inaificiener J] > 18 paral step | >) nauticieney reser, MeasureACTH fe —————_| Ss ae 7 Loworinappropritely roma igh Seconcryacrenainauticieney | Primary adrenal nsficiency FIGURE 5. Agorthmiarthedigrst otadenal rtluengy. ACH adrnocorcoropic hormoneDisorders of the Adrenal Glands |_ Glucocorticoid Medication (hours) Inflammatory Potency Potency” Hydeocarigone 20 na 1 125 | Pradisolonel 5 1836 4 vaso precnsone hehe la 1836 5 ° Dexamethasone 07s 3654 2550 0 [Fas etirmioy pane ramets oeansone co row to dose: Tavate16 clinical response with goalof sno signs or symptom af comtzal | eticiency or excess (increase doseit | Symptom af cartes deficiency tamsin, dacrensaif CS signs anc ymaptoms ae present) Mineralocontcoid Fludrocontisone (.05-0.2 mg ence dally in hemorning How t cas Tirate to 1. Normal BP 2, Normal conum Na, ‘Adrenal andeogen | ones 25-501mg once daly [yee rr tt etree ant inte ate dose of intravenous hydiveostisone (100 mg), follewed by * nuravencus hydrocortisone (1D0 mg) every 8 hours for the hhext 24 hours, with subsequent dosing governed ty clinical status, Patients with concomitant untreated adrenal insulf ciency and hypothyroidism should always receive glucocorti ciel replacement therapy frat to prevent precipitation of adre nal crisis by thyroid hormone replacement. Patents should alo be counselled to wear a medic alert identification at all as Basal Dose Considerations Glucocoticoid® “Sick day rues" | vydrocorisone Usually 15-25g/¢, divided inca Patlentfolowsat home | 23 doses ove'the day Prednisone Prednisone mgonce daily Forminer physiclosic sess (upper respiratory infection fever minor ssirgonyunderlocal anesthesia) 2-3 umes basal dose for 2-9 days Sresedosing Heath care providers follow while pavertisinthe hosprat Formedersto physiologic aress(minor or mederate surgery with ‘sonora anestooss) Hydrocortisone 25-75 maf orally or IV for 1-2 days Formajor phyziclogiestess (major surgery, waum etal lness oF chikdirnh Hydrocortisone 100 mg IV foloned by 50 mg avery 6 h1V: rapid tapering and awich te orl regimen deperding oncinical state Fludrocortzone’s not required if tyeroconisone doseis 240 mak Consider DHEA for women with impaired mood or zonee of we boing wien glucacosicaidreplacoerent has been optmized times, No increase in mineralocorticoid dose fs necessary swith illness. The term “adrenal fatigue” 1s used by some alternative medicine providers (o represent a constellation of symp: toms purported to occur in patients who experience ‘chronic emotional or physteal stress thal are claimed to be caused by simultanicous hyper- and hypocortisolism. There fie evidence to support such a condition. Patients may undergo salivary cortisol testing, butInterpretation of the results Js often unreliable. Some patients labeled with *adrenal fatigue” are given hydracor sone therapy oF animal-derived adrenal gland extract that may contain active glucocorticoid, leading to exogenous, suppression of ACTH production and iatrogenic Cushing, syndrome. Sudden discontinuation of these products can, lead to acute adrenal insufficiency. Patients with “adrenal fatigue” should be carefully tapered off any glucocorticoid therapy and other poteatial causes for thelr sympcoms explored. ‘REPOS ee ‘The most common cause of primary adrenal insull cieney is autoimmune destruction ofa layersot the adrenal cortex leading to progressive mineralecorticoid, slucocorticoid, and adrenal androgen deficiency. + Both glucocorticoid and mineralocorticoid therapy is required for treatment of primary adrenal insufficiency. + Patients cannot mount an appropriate inerease in corti solswith illness and therefore instruction in “sick day” rales regarding gucocorticoid dosing i essential to pre vent adrenal crisis. Adrenal Function During Critical Iliness Daring times of physiolegic stress, the hypothalamic pituitary-adveral axis is stimulated to precce increased levels ofcortso. In some patients the increase fn cortisol Sccrction is thought to be suboptimal ana termed “relative A." These is debate, however, a to whether the entky of relative adrenal insulficiene is a rue disease. Cortisol binding globulin and albumin decrease in critica tines, lowering the meisured total cortisol. There is no agree tment on a set of diagnostic criteria for relative At despite the ability to measure free cortisol, calculated free corti sol and basal and ACT1/-stimlated total cortiso level in Critically il patients. Stades todatedo not show improved survival in patients with relative AU treated wit high dose giucocartievid terapy. Reversa of shock, however, ray be improved, and hence iscurrenty recommended that stress dose hydrocortisone be administered to patients with svock that is esistint to standaré fund ane sasopressor therapy. ED Adrenal Mass Incidentally Noted Adrenal Masses An adieralincidentalomais defined as an adrenal massgrealer than 1 em in diameter that is detected on imaging performed for purposes other than suspicion of adrenal disease. ‘the prevalence of adrenal incidentaloma increases with age and is estimated to be approximately 10% in those 70 years of age or older, Mest lesionsare benign, nonfunctioning adenomas, and approximately 10% to 15% secrete excess hormones. Other causes include metastases (probability increases if known Disorders of the Adrenal Glands primary malignan ), myelolipoma, cysis, and adrenocortical ‘The finding of an incidental adrenal mass prompts two sain questions: (1 Isit secreting excess hormone (aldosterone, cortisol catecholamines)? and (2) Ts it benign or malignant? Patients with hypertension or with hypokalemia require test, ing for peimary aldosteronism. Biochemical testing for pheo hromocytom, such as 4 21-hour urine (oki! metanephirine ‘measurement, should be undertaken i all patients, even in the absence of typical symptoms or hypertension, All patients should also be evaluated fbr subelinieal Cushing syndrome, a condition characterized by ACTH Independent cortisol secretion that may result in metabolic (hypenplycemin and hypertension) and hone (osteoporosis) effects hypercortisolism, but not the more specific clinical features of Cashing syndrome, such as supraclavicular fat pads, wide violaceous striae, facial plethora, and proximal, muscle weakness. Init testing for subclinical Cushing syn- drome is achieved with a 1-mg overnight dexamethasone suppression text, with a cortisol level greater than 5 pg/dl (138 nmol) considered a positive test Following a positive result, further tests are required to confirm cortisol auton ‘omy and may include measurement of ACTH (suppressed). DHEAS flow). 28 hoururine free cortisol, and an 8-mg over ‘night dexamethasone suppression test; referral an endo- crinologist is recommended at this point. The decision whether 9 proceed to adrenalectomy should take inte account the risks Versus benefits of surgery. Studies to date have not heen robust enough (0 show clear postoperative lly important outcomes but suggest improved glucose, lipid, blood pressure, and bone density ‘measurements Imaging, Lindings can help differentiate between & benign and a malignant adrenal mass (Gee Table 28). Most adrenyeortleal carcinomas measure more than 4 em at the time of discovery. Approximately 75% of benign adrenal ‘masses, however, are also in this size range, Approximately 66% of benign adenomas are liptd-rich and exhbst low attenuation (10 IU) on CT imaging, Benign adrenal adeno ‘mas also exhibit apld washout (250%) of contrast material compared to non- benign lesions. Adrenal biopsy has a lim ited role in evaluation of ineidentalomas and is reserved for lesions suspicious for metastases or an infiltrative process, sach as jymphoma or infection. Phecchromocytomas should be ruled out prior to biopsy to avoid the possibility, (of a hypertensive crisis. Biopsy should not be performed shen there is suspicion for primary adrenocortical carci oma because, without review of the whole specimen, pathology cannot reliably distinguish this from a benign cortical adenoma, and tumor seeding is possible. Ifthe for- rer is suspected, the diagnosis should be established by adrenalectomy: 45An algorithm for management of adrenal incidentaloma, Including monitoring of lesions that do not require adrenale ‘omy, is shown in Figure 6. * Allpatients with adrenal incidentaloma should be eval uated for pheochromocytoma; those with hypertension ‘or hypokalemia should also be evaluated for primary aldosteronism, and all patients should be evaluated for subelinieal Cushing syndrome. * Imaging findings can help diflerentiate between a benign and malignant adrenal mass. Adrenocortical Carcinoma Adrenocortical carcinoma (ACC) is rare, aggressive turnor that often secretes excess cortisol and/or androgens. Patients may present with rapid onset of Cushing syndrome, with or without Virlizaton andor symptoms from masseffece, uch as inerewsed sbdominal girth and lower extremity edema. ty percent of AcCssecrete cortisol 20% secrete multiplehormones, including cortisol and aldosterone precursors; and Jess than 10% seerete akfosterone. Some ACCs are discovered asan incidental adre nal mass that i either indeterminate o suspicious for ACC (see Table 28). Lesions are often lange (4 em), and disease isat an advanced stage at the time of diagrosis. For localized disease, first-line therapy includes open reseeston. Debulking surgery, rriation therapy, and/or chemotherapy may also be options {ir palliation in advanced ACC Mitotane isan adrenolycic agent commonly used as ad vant therapy that hasbeen shown to be associated with loner recurrence free survival. Mitotane causes primary Al, and daily glucocorticoid replacement therapy is requited, often in supraphysiologie doses, dae {0 mitotane induced accelerated metabolism of glucocorticaids. Some patients also develop losterone deficiency manifested by hyponatremia, hyper kkalemia, elevated renin levels, and postural hypotension, requiring fludrocortisone replacement, Five-year survival rates range from 62% to 82% for thoxe with disease conned (0 the dveral gland and 13° for tumors associated with distant metastases Inde oes imeging Penerype? | I Fors Bion Stpicious Sire chm S00 stem Imesing Phenotype = Deroy <10H" + enaty>10 HU 5 Een eM eect Indications for Adenlectomy I Sere mine S208 00 nF Suspicious raging amon Euston Growt>t enfyear Funcionng tuners: I L “et fer Hormone ace one + Aideserone produce scenal tenor folow ur Conia ‘Adestrone: cee Ce «Sadie CS wih complstons Pan ee Al poor Hor Ber2monne ox LOST Tos PRAAC Senora for "Zens Cotchoamines: padogens Wolpert sno apace! + Text Pasmacr Test OHS, Wine metnopises, | tenesterore, Wire cechelamne | Srdrstenedone FIGURE 6. flgorthn fete ial dacnosiceauton ad illowupaf a neta sulle; TU =hyperersion, HU =Hovasfeldunts PRA plsma erin tity ‘ction oe asin LOST = lon dose "lr oe xed ining Fimnsapcsi apse itaen gis: ieee Posting suse ete hei eae ci apie) oor fa rtp opnapial tena "ene ein ng pci ed minora gee ‘tical kd nl Sith nti pe 46 sy roted adrenal mas CS= Cushing same: DHEAS = dehyhoepandaserene 3} dexamethasone spores est PAC = phsmaldesteoneconentaton