Hauptseite USMLE Step 2 CK Lecture Notes 2019: Internal Medicine

USMLE Step 2 CK Lecture Notes 2019: Internal Medicine

0 / 0
How much do you like this book?
What’s the quality of the file?
Download the book for quality assessment
What’s the quality of the downloaded files?
The only official Kaplan Lecture Notes for USMLE Step 2 CK cover the comprehensive information you need to ace the USMLE Step 2 and match into the residency of your choice.

Up-to-date. Updated annually by Kaplan's all-star faculty.
Highly illustrated. Includes color images and tables.
Integrated. Packed with bridges between specialities and basic science.
Learner-efficient. Organized in outline format with high-yield summary boxes.
Trusted. Used by thousands of students each year to succeed on the USMLE Step 2.
Kaplan Publishing
ISBN 13:
EPUB, 6,00 MB
Herunterladen (epub, 6,00 MB)

Es kann für Sie interessant sein Powered by Rec2Me


Am meisten angefragte Begriffe


Sie können die Buchrezension schreiben oder über Ihre Erfahrung berichten. Ihre Meinung über das gelesene Buch ist interessant für andere Leser. Unabhängig davon, ob Sie das Buch mögen oder nicht, kann Ihre ehrliche und ausführliche Beschreibung anderen Leuten beim Suchen von Büchern helfen.


PDF, 22.01 MB
0 / 0

            USMLE® Step 2 CK: Internal Medicine

            Lecture Notes




            USMLE® is a joint program of the Federation of State Medical Boards (FSMB) and the National Board of Medical Examiners (NBME), neither of which sponsors or endorses this product.

            This publication is designed to provide accurate information in regard to the subject matter covered as of its publication date, with the understanding that knowledge and best practice constantly evolve. The publisher is not engaged in rendering medical, legal, accounting, or other professional service. If medical or legal advice or other expert assistance is required, the services of a competent professional should be sought. This publication is not intended for use in clinical practice or the delivery of medical care. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book.

            © 2018 by Kaplan, Inc.

            Published by Kaplan Medical, a division of Kaplan, Inc.

            750 Third Avenue

            New York, NY 10017

            All rights reserved under International and Pan-American Copyright Conventions. By payment of the required fees, you have been granted the non-exclusive, non-transferable right to access and read the text of this eBook on screen. No part of this text may be reproduced, transmitted, downloaded, decompiled, reverse engineered, or stored in or introduced into any information storage and retrieval system, in any form or by any means, whether electronic or mechanical, now known or hereinafter invented, without the express written permission of the publisher.


            ISBN-13: 978-1-5062-3625-4


Table of Contents

	USMLE Step 2 CK Lecture Notes 2019: Internal Medicine


	Titl; e Page



	Chapter 1: Preventive Medicine

	Cancer Screening

	Travel Medicine




	Abdominal Aortic Aneurysm

	Hypertension, Diabetes Mellitus, and Hypercholesterolemia

	Alcohol Abuse

	Violence and Injury

	Chapter 2: Endocrinology

	Diseases of the Pituitary Gland

	Diseases of the Anterior Pituitary

	Diseases of the Posterior Pituitary

	Diseases of the Thyroid Gland

	Diseases of the Parathyroid Glands

	Disorders of Carbohydrate Metabolism

	Diseases of the Adrenal Gland

	Diseases of the Testes, Hypogonadism

	Chapter 3: Rheumatology

	Evaluating a Patient with Arthritis

	Tests in Rheumatologic Disease

	Rheumatoid Arthritis

	Systemic Lupus Erythematosus

	Drug-Induced Lupus


	Sjögren Syndrome

	Seronegative Arthropathies, Spondyloarthropathies


	Crystal-Induced Arthropathies

	Septic Arthritis

	Vasculitis Syndromes

	Inflammatory Myopathies

	Chapter 4: Gastroenterology

	Diseases of the Esophagus

	Epigastric Pain

	Inflammatory Bowel Disease


	Malabsorption Syndromes

	Diverticular Disease


	Colon Cancer

	Gastrointestinal Bleeding

	Acute Pancreatitis

	Autoimmune Pancreatitis

	Liver Disease and Cirrhosis

	Chapter 5: Cardiology

	Acute Chest Pain/Chest Discomfort

	Ischemic Heart Disease

	Acute Coronary Syndrome

	Congestive Heart Failure (CHF)

	Valvular Heart Disease


	Pericardial Disease

	Rate and Rhythm Disturbances

	Drugs for Cardiovascular Disease

	Shock Syndromes

	Chapter 6: Hematology


	Microcytic Anemia

	Macrocytic Anemia

	Hemolytic Anemia

	Aplastic Anemia

	Acute Leukemia

	Chronic Leukemia

	Plasma Cell Disorders


	Platelet Disorders


	Chapter 7: Infectious Diseases


	Central Nervous System Infections

	Head and Neck Infections

	Lung Infections

	Gastrointestinal Infections

	Acute Viral Hepatic Infections

	Genital and Sexually Transmitted Infections

	Urinary Tract Infections

	Bone and Joint Infections


	Lyme Disease

	Rocky Mountain Spotted Fever

	Acquired Immune Deficiency Syndrome (AIDS)

	Toxic Shock Syndrome


	Tropical Diseases



	Chapter 8: Nephrology

	Diagnostic Testing in Renal Disease

	Acute Kidney Injury

	Glomerular Diseases

	End-Stage Renal Disease


	Cystic Kidney Disease


	Fluid and Electrolyte Disorders

	Acid/Base Disturbances

	Chapter 9: Pulmonology

	Diagnostic Tests

	Disturbances in Gas Exchange

	Chest Radiography


	Obstructive Diseases

	Interstitial Lung Disease

	Pulmonary Thromboembolism

	Acute Respiratory Distress Syndrome (ARDS)

	Sleep Apnea

	Lung Cancer


	Chapter 10: Emergency Medicine

	Basic Life Support (Cardiopulmonary Resuscitation)

	Cardiac Dysrhythmias



	Alcohols (Methanol and Ethylene Glycol)

	Carbon Monoxide (CO)

	Caustics/Corrosives (Acids and Alkali)

	Drugs of Abuse

	Heavy Metals




	Tricyclic Antidepressants

	Anticholinergic Poisoning



	Head Trauma

	Subarachnoid Hemorrhage


	Radiation Injuries



	Venomous Bites and Stings

	Chapter 11: Neurology

	Spinal Cord Compression


	Subacute Combined Degeneration

	Anterior Spinal Artery Occlusion

	Brown-Séquard Syndrome

	Cerebrovascular Accident (CVA)

	Seizures and Epilepsy

	Vertigo and Dizziness

	Disorders Associated with Headache

	Guillain-Barré Syndrome (GBS)

	Myasthenia Gravis

	Amyotrophic Lateral Sclerosis

	Multiple Sclerosis


	Huntington Disease

	Parkinson Disease

	Benign Essential Tremor

	Restless Leg Syndrome

	Chapter 12: Dermatology

	Bullous/Blistering Diseases

	Drug Eruptions/Hypersensitivity


	Parasitic Infections

	Toxin-Mediated Diseases

	Benign and Precancerous Lesions

	Malignant Diseases

	Scaling Disorders (Eczema)/Papulosquamous Dermatitis

	Decubitus (Pressure) Ulcers



	Chapter 13: Radiology/Imaging

	Chest X-Ray

	Common Disorders Seen on Chest X-Ray

	Abdominal X-Ray

	PET Scanning

	Central Nervous System Visualization

	Bone Imaging

	Chapter 14: Ophthalmology

	Retinal Diseases



	Conjunctival Diseases


	Periorbital Cellulitis




	Table of Contents

	Start of Content


                	Joseph J. Lieber, MD

                    Director of Medicine

                	Elmhurst Hospital Center


                	Associate Professor of Medicine

                	Associate Program Director of Medicine for Elmhurst Site

                	Icahn School of Medicine at Mt. Sinai

                	New York, NY


                	Frank P. Noto, MD

                    Assistant Professor of Internal Medicine,  Department of Hospital Medicine


                    Associate Program Director of Education for Elmhurst Site Icahn School of Medicine at Mt. Sinai




                    Internal Medicine Clerkship and Sub-Internship Site Director

                    Icahn School of Medicine at Mt. Sinai

                	New York, NY



            The editors would like to acknowledge 

            Manuel A. Castro, MD, AAHIVS, Amirtharaj Dhanaraja, MD, Aditya Patel, MD,
                 Irfan Sheikh, MD, and Frazier Stevenson, MD for their contributions.


Preventive Medicine


            Learning Objectives

                	Describe appropriate screening methods as they apply to neoplasms of the colon, breast, cervix, and lung

                	Describe epidemiological data related to incidence and prevention of common infectious disease, chronic illness, trauma, smoking, and travel risks



Cancer Screening

        A 39-year-old woman comes to the clinic very concerned about her risk of developing cancer. Her father was diagnosed with colon cancer at age 43, and her mother was diagnosed with breast cancer at age 52. She is sexually active with multiple partners and has not seen a physician since a car accident 15 years ago. She denies any symptoms at this time, and her physical examination is normal. She asks what is recommended for a woman her age.

        Screening tests are done on seemingly healthy people to identify those at increased risk of disease. Even if a diagnostic test is available, however, that does not necessarily mean it should be used to screen for a particular disease.

            	Several harmful effects may potentially result from screening tests.

            	Any adverse outcome that occurs (large bowel perforation secondary to a colonoscopy) is iatrogenic.

            	Screening may be expensive, unpleasant, and/or inconvenient.

            	Screening may also lead to harmful treatment.


        Finally, there may be a stigma associated with incorrectly labeling a patient as “sick.”

        For all diseases for which screening is recommended, effective intervention must exist, and the course of events after a positive test result must be acceptable to the patient. Most important, the screening test must be valid, i.e., it must have been shown in trials to decrease overall mortality in the screened population. For a screening test to be recommended for regular use, it has to be extensively studied to ensure that all of the requirements are met.

        The 4 malignancies for which regular screening is recommended are cancers of the colon, breast, cervix, and lung.

Colon Cancer

        In the patient with no significant family history of colon cancer, screening should begin at age 50. The preferred screening modality for colon cancer is colonoscopy every 10 years. Other choices include annual fecal occult blood testing and sigmoidoscopy with barium enema every 5 years.

        In the patient with a single first-degree relative diagnosed with colorectal cancer before age 60 or multiple first-degree relatives with colon cancer at any age, colonoscopy should begin at age 40 or 10 years before the age at which the youngest affected relative was diagnosed, whichever age occurs earlier. In these high-risk patients, colonoscopy should be repeated every 5 years. The U.S. Preventive Services Task Force (USPSTF) does not recommend routine screening in patients age >75.

Breast Cancer

        The tests used to screen for breast cancer are mammography and manual breast exam. Mammography with or without clinical breast exam is recommended every 1–2 years from age 50–74. The American Cancer Society no longer recommends monthly self breast examination alone as a screening tool. Patients with very strong family histories of breast cancer (defined as multiple first-degree relatives) should consider prophylactic tamoxifen, discussing risks and benefits with a physician. Tamoxifen prevents breast cancer in high-risk individuals.



            Tamoxifen prevents cancer by 50% in those with >1 family member with breast cancer.

Cervical Cancer

        The screening test of choice for the early detection of cervical cancer is the Papanicolaou smear (the “Pap” test). In average risk women, Pap smear screening should be started at age 21, regardless of onset of sexual activity. It should be performed every 3 years until age 65. 



            Prostate Screening

            USPSTF concludes that the current evidence is insufficient to assess the balance of benefits/risks of prostate cancer screening in men age <75. It recommends against screening in men age >75.

            For USMLE, do not screen for prostate cancer.

        As an alternative, women age 30-65 who wish to lengthen the screening interval to every 5 years can do co-testing with Pap and HPV testing. In higher risk women, e.g., HIV, more frequent screening or screening after age 65 may be required.

Lung Cancer

        Current recommendations for lung cancer screening are as follows:

            	Annual screening with low-dose CT in adults age 55-80 who have a 30-pack-year smoking history and currently smoke or have quit within past 15 years

            	Once a person has not smoked for 15 years or develops a health problem substantially limiting life expectancy or ability/willingness to have curative lung surgery, screening should be discontinued



            Clinical Recall

                        Which of the following patients is undergoing an inappropriate method of screening as recommended by the USPSTF?

                        	A 50-year-old
                            man gets his first screening for colon cancer via colonoscopy

                        	A 50-year-old
                            woman gets her first screening for breast cancer via mammography

                        	A 17-year-old
                            woman is screened for HPV via a Pap smear after her first sexual encounter

                                        A 65-year-old man with a 30-pack-year smoking history gets a low-dose CT




                        	A 21-year-old woman with a high risk of developing breast cancer is given tamoxifen




            Answer: C



        Travel Medicine

        A 44-year-old executive comes to the clinic before traveling to Thailand for business. He has no significant past medical history and is here only because his company will not let him travel until he is seen by a physician. The patient appears agitated and demands the physician’s recommendation immediately.


        It is important to set up a pretravel counseling session 4–6 weeks before the patient’s departure.

        Hepatitis A infection is travelers’ most common vaccine-preventable disease. Hepatitis A infection is possible wherever fecal contamination of food or drinking water may occur. Infection rates are particularly high in nonindustrial countries. If a patient is leaving within 2 weeks of being seen, both the vaccine and immune serum globulin are recommended. A booster shot given 6 months after the initial vaccination confers immunity for approximately 10 years.

        All travelers to less-developed countries should get hep A vaccine.

        Hepatitis B vaccination is recommended for patients who work closely with indigenous populations. Additionally, patients who plan to engage in sexual intercourse with the local populace, to receive medical or dental care, or to remain abroad for >6 months should be vaccinated.

        Malaria: Mefloquine is the agent of choice for malaria prophylaxis. It is given once per week; it may cause adverse neuropsychiatric effects such as hallucinations, depression, suicidal ideations, and unusual behavior. Doxycycline is an acceptable alternative to mefloquine, although photosensitivity can be problematic. For pregnant patients requiring chemoprophylaxis for malaria, chloroquine is the preferred regimen.

        Rabies vaccination is recommended for patients traveling to areas where rabies is common among domesticated animals (India, Asia, Mexico). Chloroquine can blunt the response to the intradermal form of rabies vaccine. Therefore, in patients who require malaria prophylaxis, in addition to rabies prophylaxis the intramuscular form of the vaccine should be administered. Rabies vaccination is not considered a routine vaccination for most travelers.

        Typhoid vaccination is recommended for patients who are traveling to developing countries and will have prolonged exposure to contaminated food and water. Typhoid vaccination comes in 2 forms, an oral live attenuated form and a capsular polysaccharide vaccine given parenterally. The live attenuated form (1) needs to be refrigerated, and (2) is contraindicated in patients who are HIV-positive. The polysaccharide vaccine is given intramuscularly as a single injection. Side effects include irritation at the injection site. Fever and headache are rare adverse reactions to the vaccine. The polysaccharide vaccine is the preferred form for almost all subjects as it is well-tolerated and convenient (no need for refrigeration). It is safe for HIV patients.

        Polio: Adults who are traveling to developing countries and have never received a polio vaccine should receive 3 doses of the inactivated polio vaccine. Patients who have been previously immunized should receive a one-time booster. The live attenuated polio vaccine is no longer recommended because of the risk of vaccine-associated disease.

        Patients traveling to areas where meningococcal meningitis is endemic or epidemic (Nepal, sub-Saharan Africa, northern India) should be immunized with the polysaccharide vaccine. Additionally, Saudi Arabia requires immunization for pilgrims to Mecca. Patients with functional or actual asplenia and patients with terminal complement deficiencies should also receive the vaccine. Meningococcal vaccine is now routinely administered at age 11.

        To prevent traveler’s diarrhea, patients should be advised to avoid raw and street vendor salads, unwashed fruit, and tap/ice water. Patients who experience mild loose stools without fever or blood can safely take loperamide. Treatment with a fluoroquinolone or azithromycin is reserved for patients with moderate to severe symptoms.


        A 52-year-old man comes to the clinic for a health maintenance evaluation. His recent colonoscopy showed no evidence of carcinoma. Recent serum fasting glucose, serum cholesterol, and blood pressure are all within normal limits. The patient has a history of smoking and continues to smoke 2 packs per day. He was diagnosed with COPD 3 years ago.




            Patients must get Pneumovax, meningococcal, and Haemophilus vaccines 2 weeks before a splenectomy.

        Immunization is the best method available for preventing serious infectious disease. Between 50,000–70,000 adults die every year from preventable infectious disease (influenza, invasive pneumococcal disease, and hepatitis B). Surveys have shown that among patients who have an indication for any vaccination, very few actually receive it (pneumococcal vaccination 20%, influenza 40%, hepatitis B 10%). For this reason, the American College of Physicians recommends that every patient’s immunization status be reviewed at age 50; evaluate risk factors for specific vaccinations at that time.

            	Most patients received a primary immunization against tetanus and diphtheria as children. 

            	For those adults who were never vaccinated, give 3 doses. The principle is that adults require a total of 3 vaccinations against tetanus and diphtheria.
                    	Give the first 2 doses 1−2 months apart

                    	Give the third dose 6–12 months later

                    	Give a booster vaccination every 10 years for life; one of the boosters should use Tdap instead of Td
                        booster; if wound is dirty, revaccinate after 5 years




Influenza Vaccine

            vaccine is recommended annually for all adults regardless of age. Patients who have a history of cardiopulmonary disease, diabetes mellitus, or hemoglobinopathy, or are age 50+ residents of chronic care facilities will derive the greatest benefit from an annual influenza vaccination. Pregnant women who will be in their second or third trimester during the influenza season should also receive the vaccine.

Pneumococcal Vaccine

        Pneumococcal vaccine is indicated for all adults age ≥65. Additionally, the following individuals should receive the vaccine regardless of age:

            	Those with history of sickle-cell disease or splenectomy


            	Those with history of cardiopulmonary disease, alcoholism, or cirrhosis


            	Alaskan natives and certain Native American populations

                Immunocompromised patients (patients with hematologic malignancies, chronic renal failure, or nephrotic syndrome; HIV-positive patients; or patients receiving immunosuppressive medications)




        Revaccination should be performed in healthy patients who received their initial vaccination age <65 and were age <60 at the time of primary vaccination. Patients with a high risk of fatal infection (CKD, asplenic patients, immunocompromised patients) should be revaccinated 1x after 5 years. No one gets >1 booster shot per lifetime.


Hepatitis B Vaccine

        Hepatitis B vaccine is recommended when there is a history of the following:

            	IV drug abuse

            	Male homosexuality

            	Household or sexual contact with hepatitis B carriers

            	Frequent exposure to blood/blood products

            	History of chronic liver disease


        The hepatitis B vaccine is also recommended for the following individuals:

            	All children through age 18

            	Those with STIs

            	Those who are sexually active but not monogamous

            	Workers with occupational exposure to blood

            	Prison inmates


        Immunity is confirmed serologically.

Hepatitis A Vaccine

        The hepatitis A vaccine protects against the virus in >95% of cases. There are 2 types of vaccine, both of which stimulate active immunity against a future infection.

            	One contains inactivated hepatitis A virus

            	One contains a live but attenuated virus


        For the best protection, give the vaccine in 2 doses: initial dose and then a booster 6-12 months later. Protection against hepatitis A begins approximately 2–4 weeks after the initial vaccination.

        In the United States, the vaccine is strongly recommended for all children age 12–23 months in an attempt to eradicate the virus nationwide. There are also recommendations that the following populations be vaccinated:

            	All children age >1 year

            	People whose sexual activity puts them at risk

            	People with chronic liver disease

            	People who are being treated with clotting factor concentrates

            	People who are living in communities where an outbreak is present


        Hepatitis A is the most common vaccine-preventable virus acquired during travel, so people travelling to places where the virus is common (Indian subcontinent, Africa, Central America, South America, the Far East, and Eastern Europe) should be vaccinated.

Varicella Vaccine

        The varicella vaccine is a live attenuated vaccine recommended for use in all adults who lack a history of childhood infection with varicella virus. Being a live attenuated vaccine, varicella vaccine should not be given to immunocompromised patients, HIV-positive patients when symptomatic or <200 CD4 cells, or pregnant women.

        Patients age ≥60 are recommended to receive the varicella zoster (shingles) vaccine, which has been shown to reduce the risk of zoster and its associated pain (post-herpetic neuralgia). It is indicated regardless of whether there is a history of shingles, as it is possible to have a second herpes zoster infection.

Measles, Mumps, Rubella Vaccine

        The measles, mumps, rubella (MMR) vaccine is a live attenuated vaccine usually given in childhood. Healthy adults born after 1956 should receive 1 dose of the vaccine. Pregnant women and immunocompromised patients should not be vaccinated. HIV-positive patients who are asymptomatic may receive the vaccine.

Meningococcal Vaccine

        The meningococcal vaccine is recommended for everyone at age 11 visit. It is also recommended for young adults living in dormitories or barracks, people exposed to outbreaks, those with asplenia or terminal complement deficiencies, those who travel to endemic regions (traveling to Mecca), and those exposed to Neisseria meningitidis.

Human Papillomavirus (HPV) Vaccine

        The human papillomavirus (HPV) vaccine is recommended for women age 9-26, regardless of sexual activity.
            The regimen is in 3 doses: 0, 2, and 6 months. It should not be administered in pregnancy.

Herpes Zoster Vaccine

        The zoster vaccine is a live vaccine that has been shown to reduce the incidence of shingles by 50%. It has also been shown to reduce the number of cases of post-herpetic neuralgia, as well as the severity and duration of pain/discomfort associated with shingles. The vaccine is, basically, a larger-than-normal dose of the chicken pox vaccine, as both shingles and chickenpox are caused by the same virus, varicella zoster (VZV).

        The shingles vaccine (Zostavax), a live vaccine given as a single injection, is recommended for adults age ≥60, whether they have already had shingles or not. Some people report a chickenpox-like rash after receiving it. The vaccine should not be given to the following individuals:

            	Those with a weakened immune system due to HIV/AIDS or another disease that affects the immune system

            	Those who are receiving immune system-suppressing drugs or treatments, such as steroids, adalimumab (Humira), infliximab (Remicade), etanercept (Enbrel), radiation or chemotherapy

            	Those who have neoplasia, which affects the bone marrow or lymphatic system, such as leukemia or lymphoma



            Clinical Recall


                    In which of the following patients will the vaccination have the greatest benefit?
                        	Routine hepatitis A vaccination in a 2-month-old infant

                        	Influenza vaccine in a 16-year-old asymptomatic high school student

                        	VZV vaccination given to an AIDS patient with CD4 count 100

                        	Pneumococcal vaccination given to a 48-year-old male COPD patient

                        	HBV vaccination given to a heart failure patient




            Answer: D 




        A 25-year-old man comes to the clinic for evaluation of a stuffy nose and fever. Over the course of the interview the patient states that he smokes 3 packs of cigarettes per day and has been doing so for the last 7 years.

        Smoking is responsible for 1 in every 5 deaths in the United States. Smoking cessation is the most preventable cause of disease. Physicians can take the following steps to assist:

            	ASK about smoking at every visit.


            	ADVISE all smokers to quit at every visit.

            	ATTEMPT to identify those smokers willing to quit.

            	ASSIST the patient by setting a quit date (usually within 2 weeks) and using nicotine patches/gum, the oral antidepressant bupropion or varenicline as supportive therapy. Varenicline and bupropion are more effective than patches.

            	ARRANGE follow-up. If the quit attempt was successful, then provide positive reinforcement. If it was not successful, then determine why the patient smoked and elicit a recommitment to smoking cessation. Most patients require several attempts before being successful.




            Do not use varenicline in patients with a history of psychiatric disease.

        Monotherapy treatment for smoking cessation includes nicotine replacement therapy (transdermal nicotine patches, gum, lozenges, inhalers), bupropion, and varenicline. 

            	Bupropion lowers the seizure threshold so do not use in cases of alcohol abuse. 


            	Varenicline causes an increased rate of suicidal thoughts, so first screen for depression.



        Place a follow-up call 1–2 weeks after quit date. The use of pharmacotherapy doubles the effect of any tobacco cessation intervention.


        All women age >65 should be given DEXA bone density scan. Screening should begin at age 60 if there is low body weight or increased risk of fractures. A bone density test uses x-rays to measure how many grams of calcium and other bone minerals are packed into a segment of bone. The bones that are tested are typically the spine, hip and forearm. Bone density test results are reported in 2 numbers: T-score and Z-score.

        The T-score is the bone density compared with what is normally expected in a healthy young adult of the same sex. The T-score is the number of units—standard deviations—that bone density is above or below the average. 

            	T-score >2.5 SD indicates the likelihood of osteoporosis and increased risk of fracture. 

            	The diagnosis of osteoporosis by DEXA scan also means that treatment should be initiated with bisphosphonates, oral daily calcium supplementation, and vitamin D.



        The Z-score is the number of standard deviations above or below what is normally expected for someone of the same age, sex, weight, and ethnic or racial origin. 

            	Z-score ≤-2 may suggest that something other than aging is causing abnormal bone loss (consider drugs causing osteoporosis such as corticosteroids).

            	The goal in this case is to identify the underlying problem.





Abdominal Aortic Aneurysm

U/S should be done once in men age >65 who have ever smoked. There are no screening recommendations for male nonsmokers and women, regardless of smoking history.

        Hypertension, Diabetes Mellitus, and Hypercholesterolemia

        A 45-year-old man comes to the physician anxious about his health. Five years ago his mother was diagnosed with diabetes and high cholesterol. He is worried about his health and risk for heart disease. Physical examination is within normal limits.

        Cholesterol screening should commence at age 35 in men who have no risk factors for coronary artery disease. In both men and women with risk factors, screening should be done routinely after age 20. Management should not be determined by an isolated reading because cholesterol levels may fluctuate between measurements. Repeat in 5 years in low-risk individuals.

        Screening for diabetes mellitus should be considered only for patients with hypertension (>135/80 mm Hg). Diabetes mellitus is diagnosed in either of these situations:

            	Two fasting glucose measurements are >125 mg/dL, HbA1c > 6.5% 

            	Random glucose >200 mg/dL accompanied by symptoms


        There is insufficient evidence for or against routine screening. The strongest indication is for those with hypertension and hyperlipidemia.

        Screening is recommended for elevated blood pressure in those age >18, at every visit. Screening is not recommended for carotid artery stenosis with duplex.

        Alcohol Abuse

        A 55-year-old man comes to the office for evaluation of a sore throat. The patient admits that he was recently fired from his job and is having marital problems at home. The patient has no significant past medical history, and physical examination is within normal limits. He attests to drinking 3 shots of whiskey every day after work.

        Physicians should screen for alcohol abuse by using the CAGE questionnaire:

                        	Have you ever felt the need to:
                        	Cut down on your drinking?

                        	Have you ever felt:
                        	Annoyed by criticism of your drinking?

                        	Have you ever felt:
                        	Guilty about your drinking?

                        	Have you ever taken a morning:
                        	Eye opener?



        A positive screen is 2 “yes” answers. One “yes” should raise the possibility of alcohol abuse.

 Violence and Injury

        A 27-year-old woman presents to the emergency department complaining of right-arm pain. When asked how she sustained the injury, she states that she fell down the steps in front of her house. The patient appears anxious and nervous. On physical examination there are various 2 cm wide lacerations on her buttocks.

        Injuries are the most common cause of death in those age <65. The role of the physician is to advise patients about safety practices that can prevent injury, e.g., using seat belts, wearing bicycle helmets, and not driving after drinking alcohol.

        Identifying women who are at increased risk of physical or sexual abuse is an essential role for a physician. Simply asking them if they have been hit, kicked, or physically hurt can increase identification by >10%.


            Clinical Recall

                        Which of the following is indicated in a 65-year-old male smoker? 

                                    Digital rectal examination with PSA level 




                        	Meningococcal vaccination

                        	Varicella-zoster vaccination

                        	Varicella-zoster vaccination and hepatitis A vaccination

                        	Varicella-zoster vaccination and abdominal ultrasound




            Answer: E 






            Learning Objectives

                	List presenting signs and therapeutic approaches to disease of the anterior pituitary, posterior pituitary, thyroid, parathyroid, and adrenal glands

                	Describe disorders that cause hypogonadism or affect the testes

                	Describe disorders of carbohydrate metabolism



Diseases of the Pituitary Gland

        The pituitary is surrounded by the sphenoid bone and covered by the sellar diaphragm, an extension from the dura mater. It lies in the sella turcica near the hypothalamus underneath the optic chiasm.

        The pituitary is divided into 2 lobes: 

            	Adenohypophysis (or anterior lobe) (80% of pituitary) 


            	Neurohypophysis (or posterior lobe), the storage site for hormones produced by neurosecretory neurons (supraoptic and paraventricular nuclei) within the hypothalamus: ADH (antidiuretic hormone or vasopressin) and oxytocin


        There is a close relationship between the hypothalamus and the pituitary. The hypothalamus regulates the release of hormones from the anterior pituitary by different hypothalamic releasing and inhibiting hormones (hypothalamic–pituitary axis).

                    Pituitary Gland

        As a sample summary, the hypothalamus secretes releasing factors for each respective pituitary stimulatory hormone. Each pituitary hormone stimulates release of the active hormone from the final target gland. The active hormones then inhibit release of releasing factors and stimulatory hormones from the hypothalamus and pituitary gland, respectively. This is feedback inhibition, and it leads to a steady state of both respective hormones involved in the axis.

        Clinically, note the following to screen and diagnose diseases:

            	Disease states involving overproduction of target hormones lead to suppressed levels of pituitary hormones.


            	Disease states involving underproduction of target hormones lead to increased levels of pituitary hormones. 



                    Summary of Action

Diseases of the Anterior Pituitary

        Syndromes causing excess production of hormones usually arise from benign tumors of a single cell type. Microadenomas  (more common) are tumors <1 cm in diameter. Macroadenomas (less common) are tumors >1 cm in diameter. Larger tumors can occasionally compress the optic chiasm and cause visual deficits.

                    Pituitary Adenomas by Function

                        	Growth hormone (GH)






        A 32-year-old woman sees her physician because she has noticed milk-like discharge from her breasts the past 4 weeks. She also states that she has not menstruated in 2 months. The examination reveals galactorrhea but is otherwise normal.



            Cabergoline is used more often than bromocriptine because of a better side-effect profile. It is the preferred treatment for galactorrhea.

        Excess prolactin secretion is a common clinical problem in women and causes the syndrome of galactorrhea-amenorrhea. The amenorrhea appears to be caused by inhibition of hypothalamic release of gonadotropin-releasing hormone (GnRH) with a decrease in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Prolactin inhibits the LH surge that causes ovulation. The LH/FSH-producing cells are not destroyed, just suppressed. 

        Although hyperprolactinemia is also seen in men, gynecomastia and especially galactorrhea are very rare. The most common presenting symptom in men is erectile dysfunction and decreased libido. 

        Hyperprolactinemia can be seen in natural physiologic states such as pregnancy, early nursing, hypoglycemia, seizure, exercise, stress, sleep, cirrhosis, nipple stimulation, and chronic renal failure (due to PRL clearance).

        Autonomous production of prolactin occurs with pituitary adenomas; these so-called prolactinomas are the most common functioning pituitary adenomas, accounting for 60% of all pituitary tumors. They are usually microadenomas when they occur in women and macroadenomas in men, usually presenting with visual field deficits, etc. Macroadenomas can obstruct the pituitary stalk, increasing prolactin release by blocking dopamine transport from hypothalamus (stalk effect). Other examples are tumors such as craniopharyngioma, meningioma, and dysgerminoma; empty sella; and trauma.

        Hyperprolactinemia can also occur with decreased inhibitory action of dopamine. This occurs with the use of drugs that block dopamine synthesis (phenothiazines, metoclopramide) and dopamine-depleting agents (α-methyldopa, reserpine). Tricyclic antidepressants, narcotics, cocaine, SSRIs, and risperidone can also cause increased prolactin.

        Stimuli that overcome the normal dopamine inhibition can also lead to hyperprolactinemia. An example of this is primary hypothyroidism (resulting in an increase in thyrotropin-releasing hormone [TRH]) and subsequently an increase in prolactin release.

        Always check TSH in patients with elevated prolactin.

        Clinical Presentation. Hyperprolactinemia presents with galactorrhea, menstrual abnormalities amenorrhea/oligomenorrhea, osteopenia and osteoporosis in long-standing cases, infertility, and gynecomastia in women; men present with hypogonadism, erectile dysfunction, decreased libido, gynecomastia, and infertility. Men typically do not develop galactorrhea. Women are detected earlier because of menstrual symptoms. Hence, microadenomas are more common in women.

        Diagnosis. Always exclude states such as pregnancy, lactation, hypothyroidism and medications before starting the work-up of hyperprolactinemia. Prolactinomas may co-secrete growth hormone (GH).

            	Prolactin >100 ng/mL suggests probable pituitary adenoma


            	Prolactin level should be commensurate with tumor size
                    	Prolactin 100 ng/mL correlates with tumor approximately 1 cm


                    	Prolactin 200 ng/mL correlates with tumor approximately 2 cm






            A basal, fasting, morning PRL >100−200 mg/L (normal <20 mg/L) in a nonpregnant woman indicates a need for a pituitary MRI.

        Management. Treat initially with cabergoline or bromocriptine (a dopamine-agonist), which will reduce prolactin level in hyperprolactinemia. Dopamine normally inhibits prolactin release. 

            	About 90% of patients treated with cabergoline have a drop in prolactin to <10% of pretreatment levels.


            	Reserve surgery only for those adenomas not responsive to cabergoline/bromocriptine or associated with significant compressive neurologic effects.


            	Surgery is more effective for microadenomas than macroadenomas (only 30% of macroadenomas can be successfully resected, with long-term recurrence >50%).

            	Use radiation therapy if drug therapy and surgery are ineffective at reducing tumor size and prolactin level.



            Clinical Recall

                        Which of the following therapeutic options is most appropriate in the management of prolactinoma?


                        	Surgical resection

                        	Transsphenoidal resection

                        	Radiation therapy






            Answer: E 


        Acromegaly (called gigantism in children) is a syndrome of excessive secretion of growth hormone (GH). It  is an insidious, chronic debilitating disease associated with bony and soft tissue overgrowth, and increased mortality.

                    Acromegaly Facial Features
                    Wikimedia, Philippe Chanson and Sylvie Salenave

        Acromegaly is caused by a pituitary adenoma (usually macroadenoma in 75% of the cases that produce GH). Rarely ectopic tumors can produce growth hormone-releasing hormone (GHRH) and cause this syndrome. Less than 1% are malignant. GH is produced by 20% of pituitary tumors.

        Clinical Findings. GH excess occurs most frequently around decades 3-5. The following findings may be seen.

            	Various skeletal and soft tissue changes

            	Enlargement of the hands and feet, coarsening of facial features, and thickened skin folds; increase in shoe, hat, glove, and ring size

            	Enlarged nose and mandible (prognathism and separation of teeth), sometimes causing underbite

            	Deeper voice

            	Increased sweating

            	Obstructive sleep apnea

            	Enlarged internal organs, including heart, lung, spleen, liver, and kidneys

            	Interstitial edema, osteoarthritis, and entrapment neuropathy (carpal tunnel syndrome)

            	Menstrual problems (common) due to co-secretion of prolactin by GH-producing tumor

            	Cardiac anomalies (10-20%) such as hypertension, arrhythmia, hypertrophic cardiomyopathy, and accelerated atherosclerosis

            	Metabolic changes, i.e., impaired glucose tolerance (80%) and diabetes (13–20%) 

            	Hypertension (35%)

            	Headaches and visual field loss

            	Proliferated articular cartilage, causing severe joint disease




            The most common cause of death in acromegaly is cardiovascular mortality.

        Diagnosis. Patients with acromegaly have symptoms for ~9 years before the diagnosis is made. The best initial test is IGF-1 level, which is significantly elevated. The confirmatory test is GH measurement after 100 g of glucose is given orally; if GH remains high (>5 ng/mL), it is positive and suggests acromegaly. Normally, glucose load should completely suppress levels of GH.

        Measurement of insulin-like growth factor (IGF) or somatomedin correlates with disease activity.

        Radiologic studies such as MTI and CT are used to localize the tumor but should be done only after GH excess is documented biochemically. MRI is superior to CT in that it will show a tumor in 90% of people with acromegaly.

        Management. The objectives are to decrease GH levels to normal, stabilize or decrease tumor size, and preserve normal pituitary function. Transsphenoidal surgery provides a rapid response. Hypopituitarism can result in 10–20%. Primary treatment is surgery.

        Somatostatin analogues are the drugs of choice. Octreotide and lanreotide reduce GH values (70% of patients) and cause partial tumor regression (20–50% of patients). Octreotide is the best medical therapy for acromegaly. The main side effect of concern with somatostatin analogues is cholestasis, leading to cholecystitis.

        Dopamine-agonists such as bromocriptine and cabergoline are used if surgery is not curative, with 10% of patients responding to these drugs.

        Pegvisomant is a growth hormone analogue which antagonizes endogenic GH by blocking peripheral GH binding to its receptor in the liver. Important to note, pegvisomant is a second-line agent.

        Radiotherapy, used only if surgery and drug therapy do not work, results in slow resolution of disease and hypopituitarism in 20% of patients.

        Complications of acromegaly can arise from pressure of the tumor on the surrounding structures or invasion of the tumor into the brain or sinuses. Other complications include cardiac failure (most common cause of death in acromegaly), diabetes mellitus, cord compression, and visual field defects.


        Hypopituitarism is partial or complete loss of anterior function that results from any lesion which destroys the pituitary or hypothalamus or which interferes with the delivery of releasing and inhibiting factors to the anterior hypothalamus. GH and gonadotropins (FSH, LH) are typically lost early.

        Large pituitary tumors, or cysts, as well as hypothalamic tumors (craniopharyngiomas, meningiomas, gliomas) can lead to hypopituitarism. Pituitary adenomas are the most common cause of panhypopituitarism; the mass compresses the gland, causing pressure, trauma, and necrosis.

        Pituitary apoplexy is a syndrome associated with acute hemorrhagic infarction of a preexisting pituitary adenoma, and manifests as severe headache, nausea or vomiting, and depression of consciousness. It is a medical and neurosurgical emergency.

        Inflammatory diseases can lead to hypopituitarism: granulomatous diseases (sarcoidosis, tuberculosis [TB], syphilis), eosinophilic granuloma, and autoimmune lymphocytic hypophysitis (usually associated with other autoimmune diseases such as Hashimoto thyroiditis and gastric atrophy). Trauma, radiation, surgery, infections, and hypoxia may also damage both the pituitary and hypothalamus.

        Vascular diseases such as Sheehan postpartum necrosis (initial sign being the inability to lactate) and infiltrative diseases including hemochromatosis and amyloidosis may induce this state as well.

        Stroke can also damage these cells. Stroke can cause central diabetes insipidus due to damage of hypothalamus and/or posterior pituitary.

        Clinical Findings. The following hormones appear in the order in which they are lost in hypopituitarism.

            	Gonadotropin deficiency (LH and FSH) can occur in women and lead to amenorrhea, genital atrophy, infertility, decreased libido, and loss of axillary and pubic hair.

            	In men, decreased LH and FSH results in impotence, testicular atrophy, infertility, decreased libido, and loss of axillary and pubic hair.

            	GH deficiency occurs next and is not clinically detectable in adults, though it may manifest as fine wrinkles and increased sensitivity to insulin (hypoglycemia). GH deficiency gives an asymptomatic increase in lipid levels and a decrease in muscle, bone, and heart mass. It also may accelerate atherosclerosis, and it increases visceral obesity.

            	GH deficiency in children results in growth failure and short stature.

            	Thyrotropin (TSH) deficiency results in hypothyroidism with fatigue, weakness, hyperlipidemia, cold intolerance, and puffy skin without goiter.

            	Adrenocorticotropin (ACTH) deficiency occurs last, and results in secondary adrenal insufficiency caused by pituitary disease.

            	There is decreased cortisol, which results in fatigue, decreased appetite, weight loss, decreased skin and nipple pigment, and decreased response to stress (as well as fever, hypotension, and hyponatremia).


        Electrolyte changes like hyperkalemia and salt loss are minimal in secondary adrenal insufficiency because aldosterone production is mainly dependent on the renin-angiotensin system. ACTH deficiency does not result in the salt wasting, hyperkalemia, and death that are associated with aldosterone deficiency.

        Diagnosis. The first step in diagnosing pituitary insufficiency is to measure GH, TSH, LH, and IGF-1. The most reliable stimulus for GH secretion is insulin-induced hypoglycemia. After injecting 0.1 μ/kg of regular insulin, blood glucose declines to <40 mg/dL; in normal conditions that will stimulate GH levels to >10 mg/L and exclude GH deficiency. Random GH and IGF levels are not sensitive enough to diagnose GH deficiency. This is why a provocative test is used.

        Arginine infusion can also stimulate growth hormone release. Measure GH levels after infusing arginine. This is less dangerous because it does not lead to hypoglycemia.

        To diagnose ACTH deficiency, basal cortisol levels may be preserved (the problem could be only in response to stress). Insulin tolerance test is diagnostic and involves giving 0.05–0.1 U/kg of regular insulin and measuring serum cortisol; plasma cortisol should increase to >19 mg/dL. Metyrapone tests for decreased ACTH production. Metyrapone blocks cortisol production, which should increase ACTH levels. A failure of ACTH levels to rise after giving metyrapone would indicate pituitary insufficiency. Cosyntropin (ACTH) stimulation may give abnormally low cortisol output if pituitary insufficiency has led to adrenal atrophy.

        To diagnose gonadotropin deficiency in women, measure LH, FSH, and estrogen. In males, measure LH, FSH, and testosterone. To diagnose TSH deficiency, measure serum thyroxine (T4) and free triiodothyronine (T3), which are low, with a normal to low TSH.

        Management. Management of hypopituitarism involves treating the underlying causes. Multiple hormones must be replaced, but the most important is cortisol.

Empty Sella Syndrome (ESS)

        ESS is in the differential diagnosis of enlarged sella caused by pituitary tumors. In ESS, the sella has no bony erosion. It is caused by herniation of the suprasellar subarachnoid space through an incomplete diaphragma sellae. No pituitary gland is visible on CT or MRI. The syndrome can be primary (idiopathic) and is also associated with head trauma and radiation therapy. Most patients with these syndromes are obese, multiparous women with headaches; 30% will have hypertension. Endocrine symptoms are absent. Therapy is reassurance.

                    Empty Sella Syndrome


            Clinical Recall

                        What is the best initial test to diagnose acromegaly?

                        	100 g oral glucose tolerance test

                        	Insulin-like growth factor-1 levels

                        	MRI of the brain

                        	Pituitary biopsy

                        	Adrenal venous sampling




            Answer: B 



Diseases of the Posterior Pituitary

        Vasopressin (or antidiuretic hormone [ADH]) and oxytocin are synthesized in neurons of the supraoptic and paraventricular nuclei in the hypothalamus, then transported to the posterior pituitary lobe to be released into the circulatory system. A deficiency of ADH will cause diabetes insipidus (DI), while an excess of ADH will cause syndrome of inappropriate secretion of ADH (SIADH).

Diabetes Insipidus

        Diabetes insipidus (DI) often starts in childhood or early adult life. Men > women.

            	Central diabetes insipidus (CDI) is a disorder of the neurohypophyseal system, caused by partial or total deficiency of ADH. It leads to excessive, dilute urine and increased thirst associated with hypernatremia.
                    	Causes include neoplastic or infiltrative lesions of the hypothalamus or pituitary (60% also have partial or complete loss of anterior pituitary function); in the hypothalamus these lesions can be secondary to adenoma, craniopharyngioma, etc.; in the pituitary gland, adenoma, leukemia, or sarcoid histocytosis can lead to DI

                    	Other causes include pituitary or hypothalamic surgery, radiotherapy, severe head injuries, anoxia, hypertension, meningitis

                    	Idiopathic DI starts in childhood 

                    	Encephalitis, TB, and syphilis may affect the pituitary as well




            	Nephrogenic diabetes insipidus (NDI) is caused by renal resistance to the action of vasopressin. It can be idiopathic or it can be secondary to hypercalcemia, hypokalemia, sickle cell disease, amyloidosis, myeloma, pyelonephritis, sarcoidosis, or Sjögren syndrome. 
                    	Causes include drugs (lithium, demeclocycline, colchicine)





        Clinical Findings. Clinical findings of DI include polyuria, excessive thirst, polydipsia (16–20 L/d), hypernatremia with high serum osmolarity and coexisting low urine osmolarity and urine specific gravity <1.010. Nocturia is expected. 

        Hypertonicity is not usually present if the patient has an intact thirst mechanism and can increase water intake to keep up with urinary loss.

                    Posm versus Uosm during Dehydration in Normal Subjects

        Diagnosis. The water deprivation test compares Uosm after dehydration versus Uosm after vasopressin. 

            	In a normal person, the response to fluid restriction is decreased urine volume and increased urine osmolality. 

            	In DI, urine volume remains increased despite volume depletion. 

            	ADH will be decreased in central DI and increased in nephrogenic DI. If a patient falls to the right of the shaded area, the diagnosis is DI.



                    Water Restriction Test

        The differential diagnosis of DI includes primary disorders of water intake (psychogenic polydipsia, drug-induced polydipsia from chlorpromazine, anticholinergic drugs, or thioridazine) and hypothalamic diseases.

        Management. Management for CDI includes the following:

            	Hormone replacement with vasopressin subcutaneously or desmopressin subcutaneously, orally, or intranasally

            	Drugs to stimulate the secretion of ADH or increase release (chlorpropamide, clofibrate, or carbamazepine)

            	HCTZ or amiloride (for NDI) to enhance the reabsorption of fluid from proximal tubule


            	Correction of any calcium and/or potassium abnormalities


Syndromes Associated with Vasopressin (ADH) Excess

        Syndromes associated with ADH excess involve a mechanism of defense against hypovolemia or hypotension. This includes adrenal insufficiency, excessive fluid loss, fluid deprivation, and probably positive-pressure respiration.

        Excessive release of ADH from the neurohypophysis is associated with drugs or diseases (SIADH).

        Syndrome of Inappropriate Antidiuretic Hormone

        Syndrome of inappropriate antidiuretic hormone (SIADH) has many causes:

            	Malignancy such as small cell carcinoma, carcinoma of the pancreas, and ectopic ADH secretion


            	Nonmalignant pulmonary disease such as tuberculosis, pneumonia, and lung abscess

            	CNS disorder such as head injury, cerebral vascular accident, and encephalitis

            	Drugs such as chlorpropamide, clofibrate, vincristine, vinblastine, cyclophosphamide, and carbamazepine


        In general, increased ADH causes water retention and extracellular fluid volume expansion without edema or hypertension, owing to natriuresis. The water retention and sodium loss both cause hyponatremia, which is a key feature in SIADH. Hyponatremia and concentrated urine (Uosm >300 mOsm) are seen, as well as no signs of edema or dehydration. When hyponatremia is severe (sodium <120 mOsm), or acute in onset, symptoms of cerebral edema become prominent (irritability, confusion, seizures, and coma).

        Diagnosis. Lab findings in SIADH include:

            	Hyponatremia <130 mEq/L

            	Posm <270 mOsm/kg

            	Urine sodium concentration >20 mEq/L (inappropriate natriuresis)

            	Maintained hypervolemia

            	Suppression of renin–angiotensin system

            	No equal concentration of atrial natriuretic peptide

            	Low blood urea nitrate (BUN), low creatinine, low serum uric acid, and low albumin



        Management. Treat underlying causes. Restrict fluid to 800–1,000 mL/d to increase serum sodium (in chronic situations when fluid restriction is difficult to maintain, use demeclocycline which inhibits ADH action at the collecting duct [V2]). Conivaptan and tolvaptan are V2 receptor blockers indicated for moderate to severe SIADH. For very symptomatic patients (severe confusion, convulsions, or coma), use IV hypertonic saline (3%) 200–300 mL in 3–4 h. The rate of correction should be 0.5–1 mmol/L/h serum Na.


            Clinical Recall

                        Which of the following laboratory findings is suggestive of central diabetes insipidus?

                                    Increased serum osmolarity, decreased urine osmolarity, decreased ADH




                        	Decreased serum osmolarity, increased urine osmolarity, increased ADH

                                    Increased serum osmolarity, decreased urine osmolarity, increased ADH




                                    Increased serum osmolarity, increased urine osmolarity, increased ADH




                        	Decreased serum osmolarity, decreased urine osmolarity, decreased ADH




            Answer: A 



Diseases of the Thyroid Gland

        The normal function of the thyroid gland is directed toward the secretion of L-thyroxine (T4) and L-3,5,5′-triiodothyronine (T3), which influence a diversity of metabolic processes. 

        Diseases of the thyroid can be quantitative or qualitative alterations in hormone secretion, enlargement of thyroid (goiter), or both. 

            	Insufficient hormone secretion will lead to hypothyroidism.

            	Excess hormone secretion will lead to hyperthyroidism.


            	Generalized enlargement can be associated with increased, normal, or decreased function of the gland, depending on the underlying cause.

            	Focal enlargement of the thyroid can be associated with tumors (benign or malignant). 




            Clinical Pearl

            Always check free T4 to assess thyroid function.

        The most sensitive test in thyroid diseases is the TSH. If TSH is normal, then the patient is euthyroid.

        Total T4 and T3, however, does not always reflect actual thyroid function. 

            	Increased TBG levels are seen in pregnancy and the use of oral contraceptives. Total T4 will increase but free or active T4 level will be normal. 


            	Decreased TBG levels are seen in nephrotic syndrome and the use of androgens. Total T4 will decrease but free or active T4 will be normal, with the patient being euthyroid.


                    Pathways for Synthesis and Secretion of Thyroid Hormones

        RAIU (thyroid-reactive iodine uptake) varies directly with the functional state of the thyroid. After 24 hours, normal uptake is 5–30% of administered dose. 

        RAIU is increased in Graves’ disease or toxic nodule and decreased in thyroiditis or surreptitious ingestion of thyroid hormone.

                    Evaluating Thyroid Function
                        	Thyroid Hormones 

                            and TSH
                        	RAI Uptake Scan

                                	Decreased TSH

                                	Free increased T4; increased T3


                        	Increased RAIU
                        	De novo synthesis of hormone (primary hyperthyroidism)


                                	Decreased TSH

                                	Free increased T4; increased T3



                        	Decreased RAIU 

                        	Factitious hyperthyroidism or inflammation/destruction of the gland releasing preformed hormone into the circulation (subacute thyroiditis)


                                	Decreased TSH

                                	Free decreased T4; decreased T3


                        	Decreased RAIU

                        	Secondary or tertiary hypothyroidism



        Other tests include antimicrosomal and antithyroglobulin antibodies, which are detected in Hashimoto thyroiditis. In Graves’ disease, thyroid-stimulating immunoglobulin (TSI) is found. Serum thyroglobulin concentration can be used to assess the adequacy of treatment and follow-up of thyroid cancer, and to confirm the diagnosis of thyrotoxicosis factitia.

Hyperthyroidism (Thyrotoxicosis)

        A wide range of conditions can cause hyperthyroidism, although Graves’ disease is the most common. Graves’, an autoimmune disorder, causes the production of antibodies (thyroid stimulating immunoglobulin [TSI]), which stimulate the thyroid to secrete T4 and T3. 


            Clinical Pearl

            Physical Exam: Hyperthyroid Patient

            Painless & diffuse enlargement = Graves’

            Painful & diffuse enlargement = subacute thyroiditis


            Painless & nodules = Plummer

            No thyroid enlargement or thyroid not palpated = factitious

        Intrinsic thyroid autonomy can be caused by the following:

            	Hyperfunctioning adenoma (toxic adenoma)

            	 Toxic multinodular goiter (Plummer disease), a non-autoimmune disease of the elderly associated commonly with arrhythmia and CHF

            	 Simple goiter



        Transient hyperthyroidism results from subacute thyroiditis (painful) or lymphocytic thyroiditis (painless, postpartum). 



            For treatment purposes, it is important to distinguish primary hyperthyroidism (Grave’s disease or toxic adenoma) from thyroiditis.


        Drugs such as amiodarone, alpha interferon, and lithium can induce thyrotoxicosis. Excess iodine, as may occur in people taking certain expectorants
            or iodine-containing contrast agents for imaging studies, may cause hyperthyroidism. Extrathyroid source of hormones include thyrotoxicosis factitia and ectopic thyroid tissue (struma ovarii, functioning follicular carcinoma). Rarely, hyperthyroidism can result from excess production of TSH (secondary hyperthyroidism).

                    Pretibial Myxedema, a Manifestation of Graves’ Disease
                    Courtesy of Tom D. Thacher, MD

        Graves’ disease

        Graves’ disease (toxic diffuse goiter) is hyperthyroidism with diffuse goiter, exophthalmos, and dermopathy. In Graves’, autoantibodies form and bind to the TSH receptor in thyroid cell membranes, stimulating the gland to hyperfunction (TSI).

            	Commonly affects patients age <50

            	Women > men

            	Significant genetic component, i.e., a person is more likely to be affected if they have family member with the disease

            	Commonly triggered by stress, infection, and pregnancy

            	Patients with another autoimmune disease such as type 1 diabetes or pernicious anemia are more likely to be affected

            	Smoking causes increased risk of disease and may make the exophthalmos worse


                    Proptosis and Lid Retraction from Graves’ Disease

                    Wikimedia, Jonathan Trobe, MD/University of Michigan Kellogg Eye Center

        Clinical Findings. Graves’ is associated clinically with diffuse painless enlargement of the thyroid. Additionally:

            	Nervous symptoms (younger patients) 

            	Cardiovascular and myopathic symptoms (older patients)


            	Atrial fibrillation

            	Emotional lability, inability to sleep, tremors

            	Frequent bowel movements

            	Excessive sweating and heat intolerance

            	Weight loss (despite increased appetite) and loss of strength 

            	Proximal muscle weakness (prominent symptom in many patients, and the primary reason why they see a physician) 

            	Dyspnea, palpitations, angina, and possible cardiac failure

            	Warm and moist skin

            	Palmar erythema, along with fine and silky hair in hyperthyroidism

            	Ocular signs such as staring, infrequent blinking, and lid lag

            	Menstrual irregularity such as oligomenorrhea 

            	Osteoporosis and hypercalcemia, as a result of increases in osteoclast activity


        Diagnosis of Graves’ is made on history and physical exam. Lab studies include the following:

            	Decreased TSH (but elevated TSH in secondary hyperthyroidism)

            	High serum free T4 and T3

            	Elevated RAIU (but decreased RAIU in subacute thyroiditis and factitious hyperthyroidism)

            	Elevated TSI, antithyroglobulin, and antimicrosomal antibodies


        Treatment involves relief of symptoms and correction of the thyrotoxic state. Treat adrenergic hyperfunction with beta-adrenergic blockade (propranolol). Correct the high thyroid hormone levels with an anti-thyroid medication (methimazole or propylthiouracil), which blocks the synthesis of thyroid hormones and/or by treatment with radioactive iodine. 

            	Methimazole has a longer half-life, reverses hyperthyroidism more quickly, and has fewer side effects than propylthiouracil.


            	Methimazole requires an average of 6 weeks to lower T4 levels to normal and is often given before radioactive iodine treatment; it can be taken 1x/ day.

            	Use propylthiouracil only when methimazole is not appropriate because of its potential for liver damage; it must be taken 2−3x/ day.


        For years propylthiouracil was the traditional drug of choice during pregnancy because it causes fewer severe birth defects than methimazole. However, experts now recommend that propylthiouracil be given during the first trimester only. This is because there have been rare cases of liver damage in people taking propylthiouracil. After the first trimester, women should switch to methimazole for the rest of the pregnancy. 

        For women who are nursing, methimazole is probably a better choice than propylthiouracil (to avoid liver side effects). Both drugs can cause agranulocytosis.

        The most commonly used ‘permanent’ therapy for Graves’ disease is radioactive iodine. Indications for its use (overusing antithyroid agents alone) include:

            	Large thyroid gland

            	Multiple symptoms of thyrotoxicosis

            	High levels of thyroxine

            	High titers of TSI


        Because of the high relapse rate (>50%) associated with antithyroid therapy, many physicians in the United States prefer to use radioactive iodine as first-line therapy. Patients currently taking antithyroid drugs must discontinue the medication at least 2 days prior to taking the radiopharmaceutical since pretreatment with antithyroid drugs reduces the cure rate of radioiodine therapy in hyperthyroid diseases. With radioactive iodine, the desired result is hypothyroidism due to destruction of the gland, which usually occurs 2-3 months post-administration, after which hormone replacement treatment is indicated.

        Subtotal thyroidectomy (and rarely total thyroidectomy) is indicated only in pregnancy (second trimester), in children, and in cases when the thyroid is so large that there are compressive symptoms.

Thyroid Storm

        Thyroid storm is an extreme form of thyrotoxicosis, and an endocrine emergency. It is precipitated by stress, infection, surgery, or trauma. It manifests with extreme irritability, delirium, coma, tachycardia, restlessness, vomiting, jaundice, diarrhea, hypertension, dehydration, and high fever.


            Clinical Pearl

            When large quantities of iodide are ingested by patients with hyperthyroidism, the result is thyroid hormone suppression (Wolff-Chaikoff effect).

        Treatment involves supportive therapy with saline and glucose hydration, glucocorticoids, and oxygen cooling blanket. Therapy for hyperthyroidism is also used:

            	First, give propylthiouracil. 


            	Next, give iodine to inhibit hormone release.

            	 Follow with adrenergic antagonists (e.g., β-adrenergic blockers).

            	Finally, give dexamethasone to provide adrenal support. 

            	Stop the antithyroid drugs 1–2 weeks before and after the RAI treatment, as they block the uptake of the radioactive iodine.



        The far majority of hypothyroidism has a thyroid etiology (primary). 

            	Secondary to chronic thyroiditis (Hashimoto disease) (most common cause of goitrous hypothyroidism; associated with antimicrosomal antibodies)


            	Postablative surgery or radioactive iodine, heritable biosynthetic defects, and iodine deficiency

            	Drugs such as lithium and acetylsalicylic acid

            	Amiodarone, interferon, and sulfonamides



        Suprathyroid causes of hypothyroidism include pituitary induced (secondary hypothyroidism) or hypothalamic induced (tertiary hypothyroidism).

        Amiodarone, an antiarrhythmic drug used to treat ventricular and supraventricular tachyarrhythmia, is structurally similar to T4 and contains approximately 40% iodine. Its other characteristics include:

            	Highly lipid-soluble and concentrated in the adipose tissue, muscle, liver, lung, and thyroid gland


            	High elimination half-life (50−100 days) so total body iodine stores can remain increased for up to 9 months after discontinuation of the drug

            	Thyroid abnormalities are seen in up to 20% of patients receiving long-term amiodarone therapy. (However, other research has shown that with lower doses of amiodarone, incidence of thyroid dysfunction is around 4%.) 
                    	The effects range from abnormal thyroid function test findings (without clinical hyper- or hypothyroidism) to overt thyroid dysfunction, which may be amiodarone-induced thyrotoxicosis or amiodarone-induced hypothyroidism (both can develop in apparently normal thyroid glands or in glands with preexisting abnormalities).





        Amiodarone-induced thyrotoxicosis has 2 types: 

            	Type 1 occurs in patients with underlying thyroid pathology, e.g., autonomous nodular goiter or Graves’. Treatment is anti-thyroid therapy.

            	Type 2 is a result of amiodarone causing a subacute thyroiditis, with release of preformed thyroid hormones into the circulation. Treatment is glucocorticoids.



        Amiodarone-induced hypothyroidism is due to inhibition of peripheral conversion of T4 to T3.


        Clinical Findings. 

            	In the newborn, cretinism (in 1/5,000 neonates) and juvenile hypothyroidism; persistent physiologic jaundice, hoarse cry, constipation, somnolence, and feeding problems

            	In later months, delayed milestones and dwarfism, coarse features, protruding tongue, broad flat nose, widely set eyes, sparse hair, dry skin, protuberant abdomen, potbelly with umbilical hernia, impaired mental development, retarded bone age, and delayed dentition

            	In the adult, there are stages:
                    	Early stages may include lethargy; constipation; cold intolerance; stiffness/cramping of muscles; carpal tunnel syndrome; menorrhagia

                    	Later stages may include slowing intellectual and motor activity; decreased appetite; weight gain, dry hair/skin, deeper, hoarse voice; deafness


                    	Elevated cholesterol and slow, deep tendon reflexes

                    	Possible hyponatremia and anemia


                    	Ultimately, myxedema (expressionless face, sparse hair, periorbital puffiness, large tongue, and pale, cool skin that feels rough and doughy)




        Diagnosis of hypothyroidism is made by symptoms and physical findings. Lab tests confirm diagnosis.

             Confirmation of Hypothyroid Diagnosis*
                        	Primary Hypothyroidism
                        	2 or 3 Hypothyroidism

                        	↑ TSH
                        	Normal or ↓ TSH

                        	↓ T4, ↓ FT4
                        	↓ T4, ↓ FT4

                        	T3 decreases in lesser extent
                        	Accompanied by decreased secretion of other hormones

                        	*Also seen: hypercholesterolemia, elevation of CPK, AST, hyponatremia, LDH; 12% associated with pernicious anemia



        Management. The goal with hypothyroidism is to restore the metabolic state with levothyroxine. This should be done gradually in the elderly and those with coronary artery disease. Levothyroxine (T4) should be administered with monitoring of TSH/T3, T4 levels (it takes 6 weeks after dosing changes for TSH to equilibrate).

            	If there is a strong suspicion of suprathyroid hypothyroidism with a hypothalamic or pituitary origin, give hydrocortisone with thyroid hormones.

            	In patients with suprathyroid hypothyroidism, T4 level rather than TSH is used to guide treatment.

            	Levothyroxine should be taken on an empty stomach with no other drugs or vitamins; multivitamins, including calcium and iron, can decrease its absorption.

            	If a patient has coronary heart disease that needs intervention, do the intervention (CABG or stent placement) before thyroid hormone replacement is initiated.


        During pregnancy, demand for thyroid hormones may increase and thus close monitoring of TSH and T4 should be done. Hypothyroidism during pregnancy should be treated with levothyroxine, with serum TSH goal to be kept in the lower reference range. Serum TSH should be measured at 4−6 weeks’ gestation, then every 4−6 weeks until 20 weeks’ gestation.

        Myxedema coma can result if severe, long-standing hypothyroidism is left untreated. Patients develop a hypothermic, stuporous state that is frequently fatal. It is associated with respiratory depression (CO2 retention). Myxedema coma is precipitated by cold exposure, trauma, infections, and CNS depressants. Treatment includes very high doses of T4 along with T3.


        Thyroiditis includes disorders of different etiologies characterized by inflammation of the thyroid. Each has a different clinical course, and can be associated at one time or another with euthyroid, thyrotoxic, or hypothyroid state.


            Clinical Pearl

                	Hashimoto thyroiditis presents more commonly as hypothyroidism.

                	Subacute (de Quervain) thyroiditis presents more commonly as hyperthyroidism.


        Subacute thyroiditis includes granulomatous, giant cell, or de Quervain thyroiditis. This can occur at any age, although most commonly in decades 4 and 5.

            	Likely of viral origin

            	Follows upper respiratory infection symptoms, e.g., malaise, fever, pain over the thyroid, and pain referred to the lower jaw, ears, neck, or arms


            	Thyroid gland is enlarged and firm

            	Lab findings include elevated erythrocyte sedimentation rate, decreased radioactive iodine uptake, initial elevation in T4 and T3 (due to leak of hormone from the gland) followed by hypothyroidism as the hormone is depleted

            	Differential diagnosis includes mostly Graves’ disease


        Treatment is symptomatic with NSAIDs, prednisone, and propranolol. The disorder may smolder for months but eventually subsides with return to normal function.


        Hashimoto thyroiditis is a chronic inflammatory process of the thyroid with lymphocytic infiltration of the gland. It is most often seen in middle-aged women, and is the most common cause of sporadic goiter in children. 

            	Likely caused by autoimmune factors, as evidenced by lymphocytic infiltration, increased immunoglobulin, and antibodies against components of thyroid tissue (antithyroglobulin Abs)


            	Main feature is a goiter that is painless; goiter is rubbery and not always symmetric

            	Hypothyroidism occurs

            	Diagnosis is suggested by finding a firm, nontoxic goiter on examination

            	Lab findings include metabolically normal values in early stages, then increased TSH and decreased T3 and T4.

            	High titers of antithyroid antibodies, namely antimicrosomal antibodies, are found, as are antithyroperoxidase antibodies

            	Histologic confirmation is made by needle biopsy (usually not needed)


        Treatment is L-thyroxine replacement.


        Lymphocytic (silent, painless, or postpartum) thyroiditis is a self-limiting episode of thyrotoxicosis associated with chronic lymphocytic thyroiditis. It is common in women of any age. 

            	Unclear etiology and pathogenesis


            	Thyroid is nontender, firm, symmetric, and slightly/moderately enlarged


            	Lab findings include elevated T3/T4, low RAIU, and normal ESR; if antithyroid antibodies are present, they are only in low titer


        This disease may last for 2–5 months and be recurrent (as in postpartum thyroiditis). Treatment is symptomatic with propranolol.

        Reidel thyroiditis results from intense fibrosis of the thyroid and surrounding structures (including mediastinal and retroperitoneal fibrosis).

Neoplasia of the Thyroid

        Thyroid adenomas may be nonfunctioning or hyperfunctioning. They are slow-growing over many years. 

        Thyroid adenomas can be follicular (most common; highly differentiated, autonomous nodule), papillary, or Hürthle.

        Management for hyperfunctioning adenoma includes ablation with radioactive iodine. 


        Follicular carcinoma (15–20% of all thyroid cancers) is common in the elderly. Women > men. 

            	More malignant than papillary carcinoma 


            	Spreads hematogenously with distant metastasis to the lung and bone

            	Treatment requires near total thyroidectomy with postoperative radioiodine ablation



            Clinical Pearl

            RET mutations are the mutations associated with MEN2 and familial medullary thyroid carcinomas.

        Papillary carcinoma is the most common thyroid cancer (60–70% of all thyroid cancers are papillary). It is associated with history of radiation exposure. 

            	Women > men by 2–3x

            	Bimodal frequency

            	Peaks occur in decades 2 and 3, and then again later in life

            	Slow-growing; spreads via lymphatics after many years


        Treatment is surgery (small tumors limited to single area of thyroid) and surgery plus radiation (large tumors). TSH suppression therapy with levothyroxine is also used.


        Anaplastic carcinoma (1–2% of all thyroid cancer) is seen primarily in elderly patients. Women > men. It  is highly malignant with rapid and painful enlargement; 80% of patients die within 1 year of diagnosis. This cancer spreads by direct extension.

        Medullary carcinoma (5% of all thyroid cancer) occurs as a sporadic form or familial form. It arises from parafollicular cells of the thyroid. 

            	More malignant than follicular carcinoma 


            	Often produces calcitonin (is the only thyroid cancer with elevated calcitonin)

            	Is the component of 2 types of MEN (multiple endocrine neoplasia)
                    	In MEN type IIa (Sipple syndrome), pheochromocytoma, medullary thyroid carcinoma, and (in 50% of cases) parathyroid hyperplasia occur. 


                    	In MEN type IIb, pheochromocytoma, medullary carcinoma, and neuromas occur. 




            	May occur in families without other associated endocrine dysfunctions

            	Calcitonin levels can also be increased from cancer of the lung, pancreas, breast, and colon


        The only effective treatment is thyroidectomy. 


        Thyroid carcinoma should be suspected with the following: 

            	Recent growth of thyroid or mass with no tenderness or hoarseness


            	History of radiation to the head, neck, or upper mediastinum in childhood (~30 years to develop thyroid cancer) 


            	Presence of a solitary nodule or calcitonin production

            	Calcifications on x-ray such as psammoma bodies suggest papillary carcinoma; increased density is seen in medullary carcinoma. Do thyroid function tests first; cancer is never hyperfunctioning.


        Evaluation of a solitary nonfunctioning nodule is done with fine-needle aspiration (FNA) for cytology for most patients. Five percent of nonfunctioning thyroid nodules prove to be malignant; functioning nodules are very seldom malignant. 

        The first test to do in a patient with a thyroid nodule is TSH; if that is normal, then proceed to FNA. U/S is useful to distinguish cysts from solid nodules.




            Clinical Recall

                        Which of the following is the best initial step (most sensitive test) for the diagnosis of a patient suspected of having hyperthyroidism?


                        	RAIU scan

                        	Free T4 level

                        	Free T3 level

                        	TSH level

                        	TSI including antithyroglobulin and antimicrosomal Ab




            Answer: D



Parathyroid Glands

        The function of parathyroid hormone (PTH) is to maintain extracellular fluid calcium concentration. 

            	Acts directly on the bone and kidney, and indirectly on intestine (through its effects on synthesis of 1,25-dihydroxycholecalciferol [1,25(OH)2D3]) to increase serum calcium


            	Is closely regulated by the concentration of serum-ionized calcium

            	Increases osteoclast activity, which releases calcium.

            	Inhibits phosphate reabsorption in the kidney tubule, also favoring bone dissolution and calcium release from bones 

            	Activates vitamin D, which increases the GI absorption of calcium


        Calcium regulation involves 3 tissues (bone, kidney, and intestine) and 3 hormones (PTH (hypercalcemic), calcitonin (hypocalcemic), and activated vitamin D (hypercalcemic).


        Hypercalcemia represents an increase in the total or free calcium level. About 98% of calcium is stored in bone. Calcium is absorbed from the proximal portion of the small intestine, particularly the duodenum. About 80% of an ingested calcium load in the diet is lost in the feces, unabsorbed. 

        Of the 2% of calcium that is circulating in blood, free calcium is 50%, protein bound is 40%, with only 10% bound to citrate or phosphate buffers.

        The most common cause of hypercalcemia is primary hyperparathyroidism; it is usually asymptomatic and is found as a result of routine testing. Hypercalcemia due to malignancy is caused by a PTH-like protein produced by squamous cell carcinoma of the lung or metastatic disease to the bone. Granulomatous diseases such as sarcoidosis, tuberculosis, berylliosis, histoplasmosis, and coccidioidomycosis are all associated with hypercalcemia. Neutrophils in granulomas have their own 25-vitamin D hydroxylation, producing active 1,25 vitamin D. Rare causes include vitamin D intoxication, thiazide diuretics, lithium use, and Paget disease, as well as prolonged immobilization. Hyperthyroidism is associated with hypercalcemia because there is a partial effect of thyroid hormone on osteoclasts. Acidosis results in an increased amount of free calcium. This is because albumin buffers acidosis. Increased binding of hydrogen ions to albumin results in the displacement of calcium from albumin.

        Familial hypocalciuric hypercalcemia (FHH) is a benign form of hypercalcemia. It presents with mild hypercalcemia, family history of hypercalcemia, urine calcium to creatinine ratio <0.01, and urine calcium <200 mg/day (hypocalciuria). Most cases are associated with loss of function mutations in the CaSR gene, which encodes a calcium sensing receptor (expressed in kidney and parathyroid tissue). The perceived lack of calcium levels by the parathyroid leads to high levels of parathyroid hormone. FHH is indicated by the presence of hypercalcemia at the same time with hypocalciuria. (In all other causes of hypercalcemia, elevated calcium levels in the blood are correlated with elevated calcium urine levels, as a properly sensing kidney works to excrete calcium.) No treatment is generally required, since patients are most commonly asymptomatic.

        Clinical Presentation.

            	Neurologic: decreased mental activity such as lethargy and confusion

            	GI: decreased bowel activity such as constipation and anorexia but also possible nausea and vomiting; pancreatitis due to precipitation of calcium in the pancreas (severe pancreatitis, however, is associated with hypocalcemia because of binding of calcium to malabsorbed fat in the intestine) 

            	Possible ulcer disease (unclear reasons)

            	Renal: polyuria and polydipsia due induction of NDI; calcium precipitation in the kidney, causing kidney stones and nephrolithiasis

            	Cardiovascular: hypertension (30–50% of patients); EKG will show a short QT


                    Calcium Regulation

        Treatment. For severe, life-threatening hypercalcemia, give vigorous fluid replacement with normal or half-normal saline, followed by a loop diuretic such as furosemide to promote calcium loss. 

            	Use loop diuretic only after hydration in severe cases. 


            	Use IV bisphosphonate such as zoledronate or pamidronate to inhibit osteoclasts and stimulate osteoblasts (maximum effect takes 2–3 days). 

            	If fluid replacement and diuretics do not lower the calcium level quickly enough and you cannot wait the 2 days for the bisphosphonates to work, use calcitonin for a more rapid decrease in calcium level. Calcitonin inhibits osteoclasts.


Primary Hyperparathyroidism

        Primary hyperparathyroidism represents 90% of mild hypercalcemias. It is most commonly due to adenoma of 1 gland (80%), but hyperplasia of all 4 glands can lead to primary hyperparathyroidism (20%). Parathyroid cancer is a rare cause of this disease (<1%). 

        Primary hyperparathyroidism can occur as part of MEN. 

            	In MEN type I, hyperparathyroidism, pituitary tumors (3 “Ps”), and pancreatic tumors are seen. 


            	In MEN type II, hyperparathyroidism, pheochromocytoma, and medullary carcinoma of the thyroid are seen.


        Clinical Findings. 50% of patients with hyperparathyroidism are asymptomatic. Osteitis fibrosa cystica with hyperparathyroidism occurs because of increased rate of osteoclastic bone resorption and results in bone pain, fractures, swelling, deformity, areas of demineralization, bone cysts, and brown tumors (punched-out lesions producing a salt-and-pepper-like appearance). Urinary tract manifestations of hypercalcemia include polyuria, polydipsia, stones, and nephrocalcinosis with renal failure (the polyuria and polydipsia are from NDI). Neurologic manifestations include CNS problems, mild personality disturbance, severe psychiatric disorders, mental obtundation or coma, neuromuscular weakness, easy fatigability, and atrophy of muscles. GI manifestations include anorexia, weight loss, constipation, nausea, vomiting, thirst, abdominal pain with pancreatitis, and peptic ulcer disease. Cardiovascular findings include hypertension and arrhythmias (short QT).

        Diagnosis. Lab findings will include serum calcium >10.5 mg/dL, with elevated PTH. Urine calcium elevation is common, but because of the calcium-reabsorbing action of PTH, 35% of patients may have normal levels. Serum phosphate is usually low (<2.5 mg/dL). The differential diagnosis includes all other causes of hypercalcemia, especially hypercalcemia of malignancy. In every other cause of hypercalcemia, the PTH level will be low. In primary hyperparathyroidism, PTH is always elevated.

        Imaging studies such as CT, MRI, sonography, and nuclear scan are not used to diagnose hyperparathyroidism. A nuclear parathyroid scan (sestamibi) can be used to localize the adenoma. When combined with a neck sonogram, specificity rises significantly.



            Calcitonin is an intermediary measure while waiting for IV bisphosphonate to act.

        Treatment. Medical treatment, used if surgery is contraindicated or if serum calcium ≤11.5 mg/dL and patient is asymptomatic, includes bisphosphonates (pamidronate). 

            	Reduce dietary calcium to 400 mg/d


            	Give oral hydration with 2–3 L of fluid

            	Give phosphate supplementation with phospho-soda

            	Consider estrogen for hyperparathyroidism in postmenopausal women


        Surgical removal of the parathyroid glands is effective. Imaging studies may help localize the site of the affected gland prior to surgery. 


        Parathyroidectomy should be performed if there are symptoms of hypercalcemia, bone disease, renal disease, or if the patient is pregnant. Asymptomatic mild increases in calcium from hyperparathyroidism do not necessarily need to be treated.

        In primary hyperparathyroidism, surgery is indicated if any of the following are present:

            	Symptomatic hypercalcemia

            	Calcium >11.5 mg/dL

            	Renal insufficiency

            	Age <50




        Emergency treatment for severe hypercalcemia includes IV normal saline to restore volume and rarely furosemide after hydration. Everyone gets IV bisphosphonates such as pamidronate. Bisphosphonates are useful only temporarily for hyperparathyroidism and may take 2–3 days to reach maximum effect. 

        Hungry bones syndrome is hypocalcemia that occurs after surgical removal of a hyperactive parathyroid gland, due to increased osteoblast activity. It usually presents with rapidly decreasing calcium, phosphate, and magnesium 1–4 weeks post-parathyroidectomy.

        Cinacalcet is a calcimimetic agent that has some effect in hyperparathyroidism by shutting off the parathyroids. This increases the sensitivity of calcium sensing (basolateral membrane potential) on the parathyroid. Cinacalcet is used as treatment of secondary hyperparathyroidism in hemodialysis patients. It is also indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma and in moderate-to-severe primary hyperparathyroidism unamenable to surgery.



            Primary hyperparathyroidism is due to a hyperfunction of the parathyroid glands themselves. Most commonly, there is oversecretion of PTH due to a parathyroid adenoma. The elevated PTH then causes elevated serum calcium and low serum phosphate.



            Secondary hyperparathyroidism is due to physiologic (i.e., appropriate) secretion of PTH by the parathyroid glands in response to hypocalcemia (resulting vitamin D deficiency, chronic kidney disease, etc.). Serum calcium level is low (that is what causes the elevated PTH) and serum phosphate is low (because of elevated PTH). In the case of chronic kidney failure and anuria, the phosphate—in this form of secondary hyperparathyroidism—is elevated (the kidney is unable to ‘trash’ phosphate).

            Tertiary hyperparathyroidism is seen with long-term secondary hyperparathyroidism, which can lead to hyperplasia of the parathyroid glands and a loss of response to serum calcium levels. It is most often seen in patients with chronic renal failure, and is an autonomous activity of the parathyroid glands. Treatment is sometimes surgical removal.


        Hypocalcemia is most commonly caused by hypoparathyroidism, renal failure, hyperphosphatemia, and hypomagnesemia. Drugs such as loop diuretics, phenytoin, alendronate, and foscarnet will also lower calcium levels. Renal failure causes hypocalcemia because of the loss of activated 1,25-dihydroxy-vitamin D. This leads to decreased calcium absorption from the gut. In addition, hyperphosphatemia will cause the precipitation of calcium in tissues. Low magnesium levels from malnutrition of alcoholism prevent the release of parathyroid hormone from the parathyroid glands. Alkalosis decreases free calcium levels by causing increased binding of calcium to albumin. Pseudo hypocalcemia occurs with low albumin levels. The free calcium level remains normal, while the total calcium level decreases.

        To correct for albumin, add 0.8 to calcium level for every 1 gram below 4 of albumin. Massive blood transfusion gives hypocalcemia because of binding of the calcium to the citrate in the transfused units of blood.

        Clinical Findings. Hypocalcemia results in increased neural hyperexcitability such as seizures, tetany, circumoral numbness, and tingling of the extremities. Arrhythmias may develop because of a prolonged QT. Cataracts develop for unclear reasons.

        Treatment of hypocalcemia is IV or oral calcium replacement, and vitamin D replacement as necessary.