Professional Documents
Culture Documents
ACP IM KSAP �
Endocrinology and
Metabolism
0
A CPAmerican College of Physicians
1 ®
The publication of the 17111 edition of Medical Knowledge Self-Assessment Program (MKSAP) represents nearly a half-century
of serving as the gold-standard resource for internal medicine education. It also marks its evolution into an innovative learn
ing system to better meet the changing educational needs and learning styles of all internists.
The core content of MKSAP has been developed as in previous editions-newly generated, essential information in 11 topic
areas of internal medicine created by dozens of leading generalists and subspecialists and guided by certification and recer
tification requirements, emerging knowledge in the field, and user feedback. MKSAP 17 also contains 1200 all-new, psy
chometrically validated, and peer-reviewed multiple-choice questions (MCQs) for self-assessment and study, including 84
in Endocrinology and Metabolism. MKSAP 17 continues to include High Value Care (HVC) recommendations, based on the
concept of balancing clinical benefit with costs and harms, with links to MCQs that illustrate these principles. In addition,
HVC Key Points are highlighted in the text. Also highlighted, with blue text, are Hospita/ist-focused content and MCQs that
directly address the learning needs of internists who work in the hospital setting.
MKSAP 17 Digital provides access to additional tools allowing you to customize your learning experience, including regular
text updates with practice-changing, new information and 200 new self-assessment questions; a board-style pretest to help
direct your learning; and enhanced custom-quiz options. And, with MKSAP Complete, learners can access 1200 electronic
flashcards for quick review of important concepts or review the updated and enhanced version of Virtual Dx, an image-based
self-assessment tool.
As before, MKSAP 17 is optimized for use on your mobile devices, with iOS- and Android-based apps allowing you to sync
your work between your apps and online account and submit for CME credits and MOC points online.
Please visit us at the MKSAP Resource Site (mksap.acponline.org) to find out how we can help you study, earn CME credit
and MOC points, and stay up to date.
Whether you prefer to use the traditional print version or take advantage of the features available through the digital version,
we hope you enjoy MKSAP 17 and that it meets and exceeds your personal learning needs.
On behalf of the many internists who have offered their time and expertise to create the content for MKSAP 17 and the
editorial staff who work to bring this material to you in the best possible way, we are honored that you have chosen to use
MKSAP 17 and appreciate any feedback about the program you may have. Please feel free to send us any comments to
mksap_editors@acponline.org.
Sincerely,
ii
Endocrinology and Metabolism
iii
ACP Principal Staff Terence Chan, MD
Honoraria
Patrick C. Alguire, MD, FACP 2
AstraZeneca (Canada)
Senior Vice President, Medical Education
Sean McKinney 1 Pieter A. Cohen, MD
Vice President, Medical Education Stock Options/Holdings (spouse)
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Manager, Clinical Skills Program and Digital Products Benjamin P. Geisler, MD
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Linnea Donnarumma 1 Honoraria
Staff Editor Med Link Neurology
2. Has disclosed relationship(s) with any entity producing, marketing, reselling, or Cynthia D. Smith, MD, FACP
distributing health care goods or services consumed by, or used on, patients.
Stock Options/Holdings
Merck and Co.; spousal employment at Merck
Disclosure of Relationships with any entity producing,
marketing, reselling, or distributing health care goods or Acknowledgments
services consumed by, or used on, patients.
The American College of Physicians (ACP) gratefully
Patrick C. Alguire, MD, FACP acknowledges the special contributions to the develop
Consu /tantship ment and production of the 17th edition of the Medical
National Board of Medical Examiners Knowledge Self-Assessment Program' (MKSAP" 17) made
Royalties by the following people:
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Graphic Design: Michael Ripca (Graphics Technical
Stock Options/Holdings
Administrator) and WFGD Studio (Graphic Designers).
Amgen Inc, Bristol-Myers Squibb, GlaxoSmithKline, Stryker
Corporation, Zimmer Orthopedics, Teva Pharmaceuticals, Production/Systems: Dan Hoffmann (Director, Web Services
Medtronic, Covidien, Inc., Express Scripts & Systems Development), Neil Kohl (Senior Architect),
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Chris Patterson (Senior Architect), and Scott Hurd (Manager, For information on how to apply MKSAP 17 Continuing
Web Projects & CMS Services). Medical Education (CME) credits to the Royal College
MOC Program, visit the MKSAP Resource Site at
MKSAP 17 Digital: Under the direction of Steven Spadt,
mksap.acponline.org.
Vice President, Digital Products & Services, the digital ver
sion of MKSAP 17 was developed within the ACP's Digital
Product Development Department, led by Brian Sweigard
The Royal Australasian College
(Director). Other members of the team included Dan
of Physicians CPD Program
Barron (Senior Web Application Developer/Architect),
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Kara Kronenwetter (Senior Web Developer), Brad Lord be used by Fellows ofThe Royal Australasian College
(Senior Web Application Developer), John McKnight of Physicians (RACP) to meet mandatory Continuing
(Senior Web Developer), and Nate Pershall (Senior Web Professional Development (CPD) points.Two CPD cred
Developer). its are awarded for each of the200 AMA PRA Category 1
Credits rn available in MKSAP 17. More information about
The College also wishes to acknowledge that many other using MKSAP 17 for this purpose is available at the MKSAP
persons, too numerous to mention, have contributed to Resource Site at mksap.acponline.org and at www.racp.
the production of this program. Without their dedicated edu.au. CPD credits earned through MKSAP 17 should be
efforts, this program would not have been possible. reported at the MyCPD site at ww--v.racp.edu.au/mycpd.
V
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vii
Table of Contents
ix
Female Infertility................................ 56 Diagnosis and Causes of Hypercalcemia ........ 62
Physiology of Male Reproduction .................. 57 Treatment of Hypercalcemia .................. 65
Hypogonadism ................................. 57 Hypocalcemia .................................. 66
Primary Hypogonadism ...................... 57 Clinical Features of Hypocalcemia ............. 66
Secondary Hypogonadism .................... 57 Diagnosis and Causes of Hypocalcemia ......... 66
Androgen Deficiency in the Aging Male......... 57 Treatment of Hypocalcemia................... 66
Evaluation of Male Hypogonadism ............. 58 Metabolic Bone Disease .......................... 66
Testosterone Replacement Therapy................. 58 Osteopenia and Osteoporosis ................. 66
Anabolic Steroid Abuse in Men ....................60 Vitamin D Deficiency ........................ 69
Male Infertility..................................60 Paget Disease of Bone ........................ 70
Gynecomastia ..................................60
Bibliography .................................. 71
Calcium and Bone Disorders
Calcium Homeostasis and Bone Physiology.......... 61 Self-Assessment Test. ........................... 73
Hypercalcemia.................................. 62
Clinical Features of Hypercalcemia ............. 62 Index ........................................ 137
X
Endocrinology and Metabolism High
Value Care Recommendations
The American College of Physicians, in collaboration with • Microprolactinomas in asymptomatic patients do not
multiple other organizations, is engaged in a worldwide require treatment; however, surveillance is recom
initiative to promote the practice of High Value Care mended (see Item 65).
(HVC). The goals of the HVC initiative are to improve • If the thyroid-stimulating hormone level is frankly
health care outcomes by providing care of proven benefit abnormal, additional evaluation of thyroid function
and reducing costs by avoiding unnecessary and even should be considered to determine the extent of the
harmful interventions. The initiative comprises several dysfunction; measure thyroxine (T,1) when the thyroid
programs that integrate the important concept of health stimulating hormone is elevated and measure both
care value (balancing clinical benefit with costs and thyroxine (T,il and triiodothyronine (T) when the
harms) for a given intervention into a broad range of edu thyroid-stimulating hormone is suppressed.
cational materials to address the needs of trainees, prac • There is no clinical indication for serial measurement of
ticing physicians, and patients. thyroid antibody titers to determine the need for or to
guide therapy except to monitor for residual disease in
HVC content has been integrated into MKSAP 17 in several
patients treated for thyroid cancer
important ways. MKSAP 17 now includes HVC-identified
• Radioactive iodine uptake is a measure of iodine uptake
key points in the text, HVC-focused multiple choice
by the thyroid over 24 hours; it is used to evaluate the
questions, and, for subscribers to MKSAP Digital, an HVC
cause of hyperthyroidism and is not indicated in patients
custom quiz. From the text and questions, we have gen
with normal or elevated thyroid-stimulating hormone
erated the following list of HVC recommendations that
levels.
meet the definition below of high value care and bring us
• In patients with subclinical hyperthyroidism, repeat
closer to our goal of improving patient outcomes while
assessment of thyroid function should be performed
conserving finite resources.
6 to 12 weeks after the initial tests, as the values will
High Value Care Recommendation: A recommendation to normalize in up to 30% of patients.
choose diagnostic and management strategies for patients • An elevated serum thyroid-stimulating hormone level
in specific clinical situations that balance clinical benefit indicates the diagnosis of primary hypothyroidism;
with cost and harms with the goal of improving patient thyroid imaging is not indicated unless there is concern
outcomes. for a nodule on physical examination.
• The typical pattern of euthyroid sick syndrome, nonthy
Below are the High Value Care Recommendations for the
roidal illness syndrome, or low triiodothyronine (T) syn
Endocrinology and Metabolism section of MKSAP 17.
drome is a mildly elevated thyroid-stimulating hormone
• Lifestyle modifications are a cost-effective intervention level and slightly low thyroxine (T,1) and triiodothyronine
that has been proven to decrease the risk of patients with (T) levels; this pattern should not prompt further testing
prediabetes developing type 2 diabetes by 41 °lo to 58%. in the hospital.
• The data for the role and cost-effectiveness of self-mon • After patients with euthyroid sick syndrome are dis
itoring of blood glucose levels are less clear for regimens charged from the hospital, thyroid function abnormal
without multiple daily insulin injections and noninsulin ities may persist for several weeks so follow-up thyroid
regimens; generally this should be avoided. function tests should not be repeated until 6 weeks after
• For noncritically ill patients who are eating, the use of discharge.
basal and prandial subcutaneous insulin is the preferred • A serum thyroid-stimulating hormone measurement
and safest choice for achieving inpatient glycemic con is the initial laboratory test in a patient with a thy-
trol; oral agents and noninsulin injectable agents do not roid nodule; if the thyroid-stimulating hormone is
have proven safety or efficacy data in the hospital setting. suppressed, then measurement of thyroxine (T,) and
• Isolated adult-onset growth hormone deficiency is triiodothyronine (T) should be performed, and a radio
extremely rare, and its clinical significance is debated; nuclide scan should be considered to identify "hot" or
evaluation for growth hormone deficiency should be functioning nodules, which have a very low likelihood
reserved for adults with at least one known pituitary hor of malignancy and typically do not require fine-needle
mone deficiency. aspiration.
xi
• If the thyroid-stimulating hormone level is high or vitamin D status, and is the recommended test for
normal, the radionuclide scan is unnecessary as it is vitamin D deficiency.
unlikely to reveal a hot nodule and ultrasonography is • A 25-hydroxyvitamin D level between 30 and 40 ng/mL
an inexpensive and highly effective method for strati (75-100 nmol/L) is deemed sufficient for bone health;
fication of malignancy risk for nonfunctioning thyroid most expert groups recommend screening all groups at
nodules. least once for evidence of deficiency since U.S. incidence
• Measurement of testosterone levels is not recommended is 30% to 60% of the population, however, it should not
if a patient is having regular morning erections, does not be a serial, recurring screening test.
have true gynecomastia on examination, and has a nor • Treatment for low bone mass in postmenopausal women
mal testicular examination, as it is highly unlikely that he involves lifestyle modification (maximizing weight
has testosterone deficiency. bearing exercise and avoidance of tobacco or excessive
• Mild, chronic, asymptomatic gynecomastia in the male alcohol) and vitamin D and calcium supplementation; the
patient does not warrant evaluation. need for pharmacologic therapy is based on the 10-year
• 25-Hydroxyvitamin D has a relatively long half-life of estimated fracture risk (�20% for a major osteoporotic
several weeks, is the best indicator of whole body fracture or �3% for hip fracture)(see Item 12).
xii
Endocrinology and Metabolism
Disorders of Glucose does not warrant repeat measurement. The diabetes scree11.lng
tests have several advantages and disadvantages to consider. FPG
Metabolism is cheaper and more readily available in most countries com
pared with hemoglobin A,c' but the requirement for overnight
Diabetes Mellitus fasting can be problematic. OGTT best reflects the pathophysiol
Diabetes mellitus is a chronic metabolic disease characterized ogy of diabetes by identifying postprandial hyperglycemia sec
by elevated plasma glucose levels as a consequence of insulin ondary to pancreatic beta-cell deficiency; however, the test is
deficiency, impaired action of insulin secondary to insulin time-intensive. Hemoglobin A,c testing is more convenient with
resistance, or a combination of both abnormalities. Prediabetes no fasting requirement, is unaffected by acute stress or illness,
is defined as elevated plasma glucose levels below the diagnos and provides an accurate reflection of the average plasma glu
tic criteria for diabetes, but above the normal range. cose over the previous 3 months. By contrast, hemoglobin A,c
testing can miss early glucose abnormalities, such as postpran
Screening for Diabetes Mellitus dial hyperglycemia. Another disadvantage is its decreased reli
Patients with diabetes mellitus may exhibit classic symptoms ability in the setting of anemia, hemoglobinopathies, or kidney
(polyuria, polydipsia, polyphagia), or more conm1011.ly, they can or liver disease. Furthermore, conditions that affect the turno
be asymptomatic. Diabetes screening may detect an early asymp ver of erythrocytes, such as anemias/hemoglobinopathies and
tomatic phase. Current guidelines do not recommend routine pregnancy, can affect the reliability of hemoglobin A1c.
screening for type 1 diabetes as there is no consistent evidence
that early treatment during the asymptomatic stage prevents Classification of Diabetes Mellitus
progression of the disease. Similarly, it has not been firmly estab Categories for classification of diabetes encompass a range of
lished that screening improves clinical outcomes in type 2 diabe insulin abnormalities, including absolute or relative insulin
tes. However, microvascular and macrovascular disease can be deficiency, insulin resistance, or a combination of these abnor
present at the time of diagnosis of type 2 diabetes, which is malities (Table 3).
indicative of ongoing organ damage during the asymptomatic
phase. Furthermore, there is evidence that the microvascular and Insulin Deficiency
macrovascular disease associated with type 2 diabetes may be Type 1 Diabetes Mellitus
reduced with improved glucose control early in the disease Type 1 diabetes occurs in the setting of insulin deficiency. It
course and that treatment of prediabetes may delay the onset of accounts for 5% of diagnosed diabetes cases. The underlying
type 2 diabetes. In 2008, the U.S. Preventive Services Task Force mechanism is destruction of insulin-producing pancreatic
(USPSTF) recommended screening for type 2 diabetes 011.ly in beta cells, which can be autoimmune-mediated, idiopathic, or
asymptomatic adults with a sustained blood pressure level acquired.
(treated or untreated) greater than 135/80 mm Hg. Updated Autoimmune-mediated type 1 diabetes mellitus can result
USPSTF draft guidelines from 2014 have expanded screening from a combination of genetic, environmental, and autoimmune
recommendations to all adults in primary care settings with risk factors. There is a strong association between type 1 diabetes and
factors for the development of diabetes (Table 1). In contrast, the specific HLA antigens. One or more precipitating events, such as
American Diabetes Association (ADA) recommends screening for viral infections, can trigger the autoimmune process of beta-cell
type 2 diabetes based on BM! (�25) with additional risk factors, destruction in genetically susceptible persons. Autoantibodies
including a history of gestational diabetes, or age (�45 years). (one or more) can be present at the time of diagnosis, including
antibodies to the following: islet cells, glutamic acid decarboxy
Diagnostic Criteria for Diabetes Mellitus lase (GAD65), tyrosine phosphatases IA-2 and IA-2�, insulin,
Prediabetes and diabetes can be diagnosed based on the ele and zinc transporter autoantibodies. Measurements of autoanti
vated results from one of the following screening tests repeated bodies to GAD65 and lA-2 are recommended for initial confir
on two separate occasions: fasting plasma glucose (FPG), 2-hour mation as both of these assays are highly automated. In addition,
postprandial glucose during an oral glucose tolerance test autoantibodies to GAD65 persist longer than those to islet cells
(OGTT), or hemoglobin A,c (Table 2). A random plasma glucose after the development of diabetes.
level greater than or equal to 200 mg/dL (11.1 mmol/L) with Autoimmune-mediated type 1 diabetes has classically been
classic hyperglycemic symptoms is diagnostic of diabetes and considered a disease of children and young, thin adults,
1
D i s o r d e r s of Gluco s e Metabolism
Screening criteria BMI >25• and at least one additional risk factor: 2008 guidelines:
Additional screening All patients age 45 years or older Patients age 45 years or younger with any of the
criteria other risk factors in the screening criteria
ADA= American Diabetes Association; BP= blood pressure; CVD = cardiovascular disease; GDM= gestational diabetes mellitus; IFG= impaired fasting glucose;
!GT= impaired glucose tolerance; USPSTF = U.S. Preventive Services Task Force.
Data from American Diabetes Association. Classification and diagnosis of diabetes. Sec. 2. In Standards of Medical Care in Diabetes-2015. Diabetes Care 2015;38 Suppl 1 :S8-16.
IPMID: 25537714]
din the absence of hyperglycemic symptoms, an abnormal fasting plasma glucose, OGn, or hemoglobin A l e should be confirmed by repeat testing. The same test should be
used when repeating the measurement for confirmation. If two different tests are performed and only one has abnormal results, the American Diabetes Association recommends
repeating the test with the abnormal results.
Data from American Diabetes Association. (2) Classification and diagnosis of diabetes. Diabetes Care 2015 Jan;38 Suppl:S8-S16. [PMID: 25537714 J
2
Disorders of Glucose M etabolism
TABLE 3. Classification of Diabetes Mellitus duce some insulin during a "honeymoon" phase lasting several
weeks to many months, although this is not an adequate or
Insulin Deficiency•
sustained effect. Insulin therapy is therefore recommended dur
Immune-mediated ing the honeymoon phase to reduce the metabolic stress on the
Type 1 diabetes functioning beta cells to preserve any residual function for as
LADA long as possible. Late autoimmune diabetes in adults (LADA)
presents in patients with autoantibodies to pancreatic beta-cell
Rare forms: "stiff man" syndrome, anti-insulin receptor antibodies
antigens and beta-cell destruction who did not require insulin
Idiopathic (seronegative)
initially but eventually progressed to an insulin requirement.
Acquired Patients with autoimmune-mediated type 1 diabetes are at an
Diseases of the exocrine pancreas: pancreatitis, trauma/ increased risk to develop other autoimmune diseases, such as
pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis,
thyroiditis and celiac disease most commonly. Thus, screening
fibrocalculous, pancreatopathy
for associated autoimmune diseases should be considered at the
Infections: congenital rubella
time of diagnosis and/or the development of signs and symp
Drug-related: Vacor (rat poison), intravenous pentamidine toms. Consensus on the frequency and effectiveness of repeat
Insulin Resistance screening for associated autoimmune diseases is lacking.
Idiopathic type 1 diabetes can present with relative insu
Type 2 Diabetesb
lin deficiency and episodic DKA without evidence for autoim
Ketosis pronec munity. There is a strong genetic history of diabetes, and Asian
Other or Rare Types
I and African ancestry appears to be a predisposing factor.
Acquired type 1 diabetes can be caused by diseases affect
Genetic defects in beta-cell function (including six distinct
MODY syndromes) ing the exocrine pancreas, infections, or drugs. Diffuse dam
age to the pancreas and beta cells or impaired insulin secretion
Genetic defects in insulin action
with subsequent insulin deficiency occurs in these scenarios.
Endocrinopathies:
KEY POINTS
(acromegaly, Cushing syndrome, glucagonoma,
pheochromocytoma, hyperthyroidism)d • Prediabetes and diabetes mellitus can be diagnosed
(somatostatinoma, aldosteronoma) ° based on the elevated results from one of the following
Drug-related: screening tests repeated on two separate occasions: fast
ing plasma glucose, 2-hour postprandial glucose during
(glucocorticoids, thiazides, �-blockers, diazoxide, tacrolimus,
cyclosporine, niacin, HIV protease inhibitors, atypical an oral glucose tolerance test, or hemoglobin A 10 .
antipsychotics [clozapine, olanzapine])f
• Measurements of autoantibodies to GAD65 and IA-2 are
Genetic syndromes: recommended for initial confirmation of autoimmune
Down syndrome9 mediated type 1 diabetes mellitus.
Wolfram syndrome (DIDMOAD)h
(Klinefelter, Turner, and Prader-Willi syndromes; myotonic Insulin Resistance
dystrophy)d
Insulin resistance is characterized by the inability of the
DIDMOAD = diabetes insipidus, diabetes mellitus, optic atrophy, and deafness; LADA: peripheral cells to utilize insulin effectively, with a compensa
late autoimmune diabetes in adults; MODY= maturity-onset diabetes of the young.
3
Disorders of Glucose Metabolism
' TABLE 4. AHA/NHLBI Criteria for the Definition of the Insulin resistance from obesity in the setting of relative
: Metabolic Syndrome insulin deficiency contributes to the development of type 2
Clinical Criteria Qualifying Measurements diabetes in the majority of patients. The degree of hyperglyce
(Must meet at least mia depends on the extent of beta-cell function, which can
3 of the 5 criteria) decline over time.
Waist circumference• Men 40in (102 cm)b
Type 2 diabetes generally has an insidious onset of pro
longed asymptomatic hyperglycemia. Most patients do not
Women 35in (89 emf
present with the classic symptoms of polydipsia, polyphagia, or
FastingTG ?:150mg/dl(1.7mmol/L)or
polyuria. Patients with type 2 diabetes may present first with
Drug therapy targeting increased TG macrovascular or microvascular changes. Although type 2 dia
HDL cholesterol Men <40mg/dl(1.0mmol/L) betes is often considered an adult disease, the incidence is
Women <50mg/dl (1.3mmol/L)or increasing along with obesity rates in children and adolescents.
Residual insulin production from the beta cells is insuf
Drug therapy targeting decreased
HDL ficient to control glucose adequately, but it is able to suppress
Blood pressure Systolic ?:130mm Hg or
lipolysis for most persons with type 2 diabetes. Under extreme
metabolic stress, such as an illness, some patients with type 2
Diastolic ?:85mm Hg or
diabetes cannot suppress lipolysis and present with DKA.
Fasting glucose Drug therapy for hypertension
Ketosis-prone patients with type 2 diabetes are more likely to
Blood glucose?: 100mg/dl be overweight or obese, middle-aged, male, and of black or
(5.6 mmol/L) or
Latino ethnicity. Insulin use during the time of metabolic
Drug therapy for increased glucose stress can often restore the beta cells from the glucose toxicity
AHA= American Heart Association; HDL= high-density lipoprotein cholesterol; with a return to diet, exercise, and oral hypoglycemic agents
NHLBI = National Heart, Lung, and Blood Institute; TG = triglycerides.
for glucose control. Prior to switching from insulin to oral
asome individuals with minimally elevated waist circumference measurements [e.g.,
(men 37-39 in or 94-99 cm) or(women 31-34 in or 79-86 cm)] may still be at risk for
therapy, pancreatic beta-cell function should be assessed with
type 2 diabetes or cardiovascular disease and will benefit from lifestyle interventions. fasting C-peptide and glucose measurements.
bA lower waist circumference of 35 in {89 cm) should be used for Asian American men. Lifestyle modifications alone or combined with therapeu
'A lower waist circumference of 31 in (79 cm) should be used for Asian American tic interventions can prevent or delay the development of type
women.
2 diabetes in high-risk persons. Lifestyle modifications are a
Data from Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management
of the metabolic syndrome: An American Heart Association/National Heart, Lung,
cost-effective intervention. Several randomized controlled tri
and Blood Institute Scientific Statement: Executive Summary. Circulation. 2005 Oct als provide evidence that diet changes, increased daily exer
25;112(17):2735-52. [PMID: 16157765]
cise, and weight loss targets of 5% to 7% can significantly
decrease the risk of developing type 2 diabetes in persons with
or more risk factors for metabolic syndrome, the Endocrine prediabetes by 41% to 58%. Additionally, metformin has been
Society recommends a 3-year screening interval for the meta shown to reduce the risk of diabetes in patients with prediabe
bolic syndrome components including waist circumference, tes, although this effect was not as robust as lifestyle interven
fasting lipid profile, fasting plasma glucose, and blood pressure. tions. In the setting of impaired glucose tolerance, impaired
Calculation of the 10-year CVD risk is recommended in persons fasting glucose values, or hemoglobin A1c values between 5.7%
with metabolic syndrome to determine the need for lifestyle and 6.4%, the ADA recommends considering metformin for
modifications and therapeutic interventions to prevent or delay prevention of type 2 diabetes.
progression to type 2 diabetes or CVD. The Framingham Risk Additional therapeutic agents, such as lipase inhibitors,
Score and the new Pooled Cohort Equation from the American a-glucosidase inhibitors, and thiazolidinediones, have been
College of Cardiology/ American Heart Association are fre evaluated to delay or prevent type 2 diabetes; however, the
quently used within the United States to assess CVD risk. effectiveness, cost, and potential side effects must be consid
ered before implementation (Table 5).
Type 2 Diabetes Mellitus
KEY POINTS
Type 2 diabetes mellitus accounts for most (90%-95%) diag
nosed diabetes cases. It affects 10.9 million (26.9%) of adults in • Lifestyle modifications are a cost-effective intervention HVC
the United States aged 65 years or older. Asian Americans, that has been proven to decrease the risk of patients with
American Indians, Alaska Natives, Hispanics, and non prediabetes developing type 2 diabetes by 41% to 58%.
Hispanic black persons are at an increased risk for developing • In high-risk persons, the American Diabetes
diabetes compared with non-Hispanic white persons. The Association recommends considering metformin for
etiology of type 2 diabetes is likely multifactorial. There is often prevention of type 2 diabetes, particularly in patients
a strong family history of type 2 diabetes among first-degree who are younger than 60 years of age, have a BMI
relatives, although the specific genes responsible for the glu greater than 35, or have a history of gestational diabetes.
cose abnormalities remain unidentified.
4
Disorders of Glucose Metabolism
TABLE 5. Strategies to Prevent or Delay Onset of Type 2 times daily initially, to include fasting and 1-hour or 2-hour
Diabetes Mellitus postprandial values. Postprandial hyperglycemia in pregnancy
Intervention Effectiveness may predict worse fetal outcomes and complications.
Lifestyle interventions and/or pharmacologic agents
Diet and exercise Sustained weight loss of 7%,
should be implemented when glucose goals for gestational
with at least 150 minutes of
moderate exercise per week, diabetes are not met. Nutrition requirements for gestational
shown to delay onset of diabetes should allow for appropriate maternal weight gain
diabetes by up to 3 years
for normal fetal growth while obtaining goal glucose values. A
Smoking cessation Modestly effective as long as moderate exercise program is recommended for glycemic
it does not cause weight gain,
but is always recommended
control.
Insulin has traditionally been the mainstay of therapy for
Bariatric surgery Effective if used in morbidly
obese persons (BMI >40) gestational diabetes when glycemic goals are not met with diet
and exercise. Off-label use of metformin and glyburide in
Metformin• Shown to delay onset of
diabetes by up to 3 years pregnancy has been studied and there appears to be equiva
Lipase inhibitors (orlistat) Shown to delay onset of
lence in efficacy with insulin; however, long-term safety data
diabetes by up to 3 years are lacking.
o.-Glucosidase inhibitors Shown to delay onset of Gestational diabetes resolves after pregnancy for most
(acarbose, voglibose) diabetes by up to 3 years women; however, the risk of developing type 2 diabetes is 5%
Thiazolidinediones Shown to delay onset of to 10% after delivery and 35% to 60% in the subsequent 10 to
(troglitazone, rosiglitazone, diabetes by up to 3 years 20 years. The ADA recommends diabetes screening for women
pioglitazone)
with a history of gestational diabetes using standard criteria at
Insulin and insulin Ineffective 6 to 12 weeks postpartum and every 3 years thereafter.
secretagogues (sulfonylureas,
meglitinides) KEY POINTS
ACE inhibitors and Ineffective • Lifestyle interventions should be implemented to meet
angiotensin receptor blockers
glycemic goals in women with gestational diabetes;
Estrogen-progestin Modest effect only however, when these are not met, insulin should be
'Preferred. initiated.
• For women with a history of gestational diabetes, diabe
tes screening using standard criteria should occur at 6
Gestational Diabetes Mellitus to 12 weeks postpartum and every 3 years thereafter.
Relative insulin deficiency during the increased insulin resist
ance associated with pregnancy can result in the development Uncommon Types of Diabetes Mellitus
of gestational diabetes mellitus. Pregnant women at high risk Genetic defects in beta-cell function and insulin action cause
for developing gestational diabetes include those from certain some uncommon forms of diabetes (see Table 3). Maturity
racial or ethnic groups (Hispanic/Latino Americans, blacks, onset diabetes of the young (MODY) is an autosomal dominant
and American Indians), overweight or obese women, women monogenetic defect that affects beta-cell function but not
older than 25 years of age, and women with a strong family insulin action. MODY should be suspected in non-obese
history of type 2 diabetes. An estimated 2% to 10% of pregnant patients with a strong family history for diabetes when the
women have gestational diabetes. Complications related to onset of diabetes occurs before 25 years of age in the absence
gestational diabetes include miscarriage, fetal deformities, of autoantibodies. Genetic defects in insulin action cause insu
large for gestational age infants, macrosomia, preeclampsia, lin resistance with varying degrees of hyperglycemia, as seen
complications during labor and delivery, increased perinatal with congenital lipodystrophy.
complications, and mortality. Complication risk is on a con Several endocrinopathies can impair insulin action or
tinuum with increasing hyperglycemia. secretion as a consequence of excess hormone production.
Disagreement exists among consensus groups regarding Conditions such as Cushing syndrome and pheochromocy
the definition, screening methods, and diagnostic criteria for toma decrease the action of insulin secondary to excess
gestational diabetes. High-risk pregnant women should be cortisol and epinephrine, respectively. The hypokalemia
screened for overt diabetes at the initial prenatal visit using induced by hyperaldosteronism can inhibit the secretion of
criteria for nonpregnant women, according to the International insulin.
Association of Diabetes and Pregnancy Study Group (IADPSG)
and the ADA. In the absence of overt diabetes at the initial Management of Diabetes Mellitus
office visit, diabetes screening should occur between 24 and The most effective management of diabetes mellitus includes a
28 weeks' gestation. Once a diagnosis of gestational diabetes is multidisciplinary approach, including patient education and
made, glucose monitoring should be performed at least four support, engaging patients in their care and decision making,
5
D i sorde rs of Glucose Metabolism
lifestyle modifications with diet and exercise, reduced caloric Patient Education
intake for overweight and obese patients, and pharmacologic Diabetes self-management education (DSME) and diabetes
therapies when necessary to meet individualized glycemic self-management support (DSMS) are recommended at the
goals (Table 6). time of diagnosis of prediabetes or diabetes and throughout
TABLE 6. American Diabetes Association Recommended Outpatient Glycemic Goals for Adults with Diabetes Mellitus
State of Characteristics of Patients Hemoglobin Preprandial Postprandial Capillary Glucose
Health A,/ Capillary (1-2 hours after meal)•
Glucose•
Healthy Early in disease course <7.0% without 70-130 mg/dl <180 mg/dL(10.0 mmol/L)
severe recurrent (3.9-7.2 mmol/L)
Few comorbidities
hypoglycemia
Preconception
(<6.S% for
Patient preference select patients)b
Moderate-to-severe impairment in
cognition and function
Limited life expectancy
Pregnant Preexisting type 1 or type 2 diabetes <6.0% without 60-99 mg/dl 100-129 mg/dL(5.6-7.1 mmol/L)
women severe recurrent (3.3-5.5 mmol/L)
hypoglycemia
Gestational diabetes :s;95 mg/dl 1-hour after meal: :s;140 mg/dL
(5.3 mmol/L) (7.8 mmol/L)
2-hours after meal: :s;120 mg/dL
(6.7 mmol/L)
a Recommended if goal can be met without severe recurrent hypoglycemia. lf severe recurrent hypoglycemia is present, there is no recommended hemoglobin A 1 , goal, as
modification of the patient's diabetes mellitus regimen to resolve severe recurrent hypoglycemia should take precedence. When severe recurrent hypoglycemia is resolved, an
hemoglobin A 1 c goal can be chosen, and treatment decisions can again be made based on that individualized hemoglobin A 1 c goal without frequent hypoglycemia.
bThis can be considered for patients with an early diagnosis of diabetes mellitus, no significant cardiovascular disease, or managed with lifestyle modifications or metformin.
Data from American Diabetes Association. Glycemic targets. Sec. 6. In Standards of Medical Care in Diabetes-2015. Diabetes Care. 2015;38(5uppl 1):533-540. [PMID: 25537705[.
(Modikation of Table 6.2 (p. 537).
Data from American Diabetes Association. Older adults. Sec. 10. In Standards of Medical Care in Diabetes-2015. Diabetes Care. 2015;38(5uppl 1):567-569. [PMID: 25537711 ].
(Modification of Table 10.1 (p. 568).
Data from American Diabetes Association. Management of diabetes in pregnancy. Sec. 12. In Standards of Medical Care in Diabetes-2015. Diabetes Care. 2015;38(Suppl 1 ):
577-579. [PMID: 25537713J.
6
Disorders of Glucose Metabolism
the lifetime of the patient. DSMS is an individualized plan that TABLE 7. Comparison of Hemoglobin A 1 c Value and
provides opportunities for educational and motivational Estimated Plasma Glucose Level
support for diabetes self-management. DSME and DSMS Hemoglobin A 1 c (%) Estimated Average Plasma
jointly provide an opportunity for collaboration between the Glucose Level
patient and health care providers to assess educational needs mg/dL(mmol/L)
and abilities, develop personal treatment goals, learn self
management skills, and provide ongoing psychosocial and 6 126(7.0)
clinical support. Improved outcomes and reduced costs have 7 154(8.6)
been associated with DSME and DSMS. 8 183(10.2)
9 212 (11.8)
Self-Monitoring of Blood Glucose
10 240(13.4)
Blood glucose monitoring can involve a variety of modalities,
including self-monitoring of blood glucose (SMBG), hemo 11 269(14.9)
globin A1 e, or continuous glucose monitoring (CGM). 12 298(16.5)
SMBG is recommended for patients on multiple daily Adapted with permission of American Diabetes Association, from Translating the
injection (MDI) insulin therapy or continuous subcutaneous A 1 C assay into estimated average glucose values. Nathan DM, Kuenen J, Borg R,
Zheng H, Shoenfeld D, Heine RJ; A1(-derived average glucose study group.
insulin infusion (CSII) therapy. SMBG should be performed !erratum in Diabetes Care. 2009;32(1 ):2071. Diabetes Care. 2008;31 (8):1476.
IPMID: 185400461
frequently during several critical time periods: preprandial,
bedtime, before and after exercise, periods of symptomatic
hypoglycemia or hyperglycemia, and before important activi CGM combined with intensive insulin therapy in adults
ties such as operating dangerous machinery. Monitoring (;;;:25 years of age) with type 1 diabetes as a successful modality
blood glucose levels 1 to 2 hours after food consumption to lower hemoglobin A1e levels. The greatest improvements in
(postprandial) can be useful to assess prandial insulin cover glycemic control are associated with longer periods of CGM
age in patients with at-goal preprandial readings but with use. In patients using a CGM system, it is important to note
hemoglobin A 1e not at goal. Overnight blood glucose monitor that it does not replace SMBG. Calibration with SMBG is
ing can help detect hypoglycemia or dawn phenomenon. required at least twice daily with CGM systems. All CGM glu
Success with SMBG requires the physician and patient to act cose values that warrant an immediate intervention should be
upon the information that it provides. This can include insu confirmed with SMBG prior to action due to a lag time ranging
lin dose adjustments, changes in meal content, or changes in from 5 to 21 minutes for several CGM brands between capillary
activity level to reach individualized glycemic goals. The data blood glucose and interstitial glucose. Rapid glucose fluctua
for the role and cost-effectiveness of SMBG are less clear for tions further increase the lag time.
regimens without multiple daily insulin injections and non KEY POINTS
insulin regimens.
• Blood glucose monitoring, including self-monitoring of
It is often necessary to combine both SMBG and hemo
blood glucose levels, hemoglobin A1c levels, or continu
globin A 1e to determine if adequate control of glucose has been
ous glucose monitoring, is recommended for patients
achieved. There is a strong correlation between hemoglobin
with diabetes mellitus requiring multiple daily insulin
A 1 e and the average 3-month plasma glucose value. Therefore,
injections or continuous intravenous insulin injection
the ADA and the American Association for Clinical Chemistry
therapy.
advocate reporting both the hemoglobin A 1e and the estimated
plasma glucose levels (Table 7). Hemoglobin A1 e monitoring • The data for the role and cost-effectiveness of self- HVC
should be measured at the time of diagnosis and every monitoring of blood glucose levels are less clear for
3 months while making changes to achieve glycemic goals. regimens without multiple daily insulin injections and
Testing intervals can be decreased to twice yearly after glyce noninsulin regimens; generally this should be avoided.
mic goals have been met.
CGM technology measures real-time glucose values from Nonpharmacologic Approaches
the interstitial fluid every few seconds through the temporary Nonpharmacologic approaches to diabetes management
placement of a sensor subcutaneously for 3 to 7 days. The sen should be implemented throughout the lifespan of the
sor is connected to a transmitter that sends the data through patient. These approaches can be used alone or as adjunct
wireless radiofrequency to a display device. CGM glucose val therapy in type 2 diabetes to improve the success rate of
ues average + /- 15% from a laboratory glucose measurement. pharmacologic agents. Medical nutrition therapy and exer
CGM may be useful in persons with frequent hypoglycemia, cise can be used in conjunction with insulin therapy for
hypoglycemic unawareness, or extreme fluctuations in glu patients with type 1 diabetes.
cose levels. CGM systems can rapidly identify hypo- or hyper Medical nutrition therapy is an essential component of
glycemia that is not always detected with SMBG or hemoglobin any successful management plan for patients with prediabetes
A 1e measurements. Additionally, the ADA endorses the use of or diabetes. Modest weight loss (2.0-8.0 kg [4.4-17.6 lb] or 7%)
7
Disorders of Glucose Metabol ism
through caloric reduction can benefit some overweight or 42% to 57%. Intensive insulin therapy has risks, including
obese adults with type 2 diabetes. significant increases in hypoglycemia and weight gain.
Consistent exercise provides beneficial effects on glucose Therapy should therefore be individually tailored for each
control, weight, and cardiovascular status. For persons with patient's preferences, lifestyle, education level, financial
diabetes in whom no contraindications exist, aerobic exercise resources, and comorbidities.
should consist of at least 150 minutes/week at a moderate Available insulin preparations and their activity profiles
intensity level, 75 minutes/week at a vigorous activity level, or are indicated in Table 8. Most persons with type 1 diabetes are
a combination of these two. Resistance training should be sensitive to the effects of exogenous insulin therapy, with ini
incorporated into the exercise routine at least 2 days per week. tial total daily doses of insulin typically ranging from 0.3 to
Hypoglycemia and extreme hyperglycemia can worsen if pre 1 U/kg/d. A basal insulin dose should account for half of the
sent at the time of exercise and should be corrected before total daily dose of insulin, while the remaining insulin should
proceeding with increased physical activity. be divided to cover the number of meals consumed during the
Bariatric surgical procedures (restrictive and bypass) can day. Basal insulin coverage can be provided with one to two
be considered in obese patients with type 2 diabetes. Weight daily injections of insulin detemir, glargine, or neutral prota
loss and diabetes remission rates are significant with these mine Hagedorn (NPH) insulin. CSII can also provide basal
procedures, but the long-term benefits require additional coverage with analogue insulin. For prandial coverage, ana
studies. See MKSAP 17 Gastroenterology and Hepatology and logue or regular insulin is injected prior to meal consumption
MKSAP 17 General Internal Medicine for more information. or analogue insulin is bolused with CSII prior to meals. Insulin
Depression, anxiety, and diabetes-related stress are com dosing immediately after a meal is appropriate in certain situ
mon among patients with diabetes and may impair their abil ations, particularly when food intake is unpredictable.
ity to achieve success with a diabetes management plan. Postprandial insulin dosing allows for a reduction in the insu
Screening should occur continuously during the course of lin dose that is commensurate with the amount of food
diabetes treatment. ingested to avoid hypoglycemia that could have resulted from
the full insulin dose. For example, the postprandial insulin
Pharmacologic Therapy dose is reduced by 50% if only half of the meal is consumed.
An individualized treatment goal will help guide the selection
of the optimal treatment regimen. For many persons with
diabetes, a reasonable goal for hemoglobin A 1 e is less than 7.0% TABLE 8. Pharmacokinetic Properties of Insulin Products•
(or less than 6.5%, if this can be achieved without significant Insulin Type Onset Peak Duration
hypoglycemia). If severe recurrent hypoglycemia is present,
Rapid-acting or 5-15 min 45-90 min 2-4h
there is no recommended hemoglobin A 1e goal, as modifica analogue (lispro,
tion of the patient's diabetes regimen to resolve severe recur aspart, glulisine)
rent hypoglycemia should take precedence. The increased Short-acting (regular) 0.5-1h 2-4h 4-8 h
risks of hypoglycemia outweigh the risks of diabetes complica NPH insulin 1-3h 4-10h 10-18h
tions in older patients with longer disease duration, which
Detemir 1-2 h Noneb 12-24h<
necessitates consideration of a less-stringent glycemic goal.
The recommended goals from the ADA for blood glucose and Glargine 2-3h Noneb 20-24+h
hemoglobin A 1e levels are located in Table 6. Pre-mixed insulins
70%NPH/30% 0.5-1h 2-10h 10-18h
Therapy for Type 1 Diabetes Mellitus regular
Lifelong insulin therapy is the first-line treatment for type 1 50% NPH/50% 0.5-1 h 2-10 hd 10-18h
diabetes. Physiologic insulin therapy, also known as intensive regular
insulin therapy, is the ideal insulin regimen as it attempts to 75%NPl/25% lispro 10-20 min 1-6 h 10-18 h
mimic the actions of normal pancreatic beta cells. Intensive 50%NPl/50% lispro 10-20 min 1-6hd 10-18 h
insulin therapy includes multiple daily injections (MDI)
70%NPA/30% aspart 10-20 min 1-6h 10-18 h
(<::3 per day) with an intermediate or long-acting insulin for
NPA = neutral protamine aspart; NPH = neutral protamine Hagedorn; NPL = neutral
basal coverage and multiple preprandial injections through protamine lispro.
out the day with analogue or regular insulin. Intensive insu aThe time course of each insulin varies significantly between persons and within
lin therapy can also include continuous subcutaneous insu the same person on different days. Therefore, the time periods listed should be
considered general guidelines only.
lin infusion (CS!!) and meal-time boluses with an insulin
bBoth insulin detemir and insulin glargine can produce a peak effect in some per
pump. Data support targeting normal glycemic levels with a sons. especially at higher doses.
goal hemoglobin A 1c of less than 7% for most persons with crhe duration of action for insulin detemir varies depending on the dose given.
type 1 diabetes to reduce long-term complications. Long dPremixed insulins containing a larger proportion of rapid- or short-acting insulin
term physiologic insulin therapy reduces early microvascular tend to have larger peaks occurring at an earlier time than mixtures containing
smaller proportions of rapid and short-acting insulin.
disease by 34% to 76% and reduces cardiovascular events by
8
Disorders of Glucose Metabolism
9
Disorders of Glucose Metabolism
TABLE 9. Pharmacologic Agents Used to Lower Blood Glucose Levels in Type 2 Diabetes Mellitus
Class Mechanism of Action Effect on Risks and Concerns Long-Term Studies on
Weight Definitive Outcomes
Biguanides (metformin)b Decrease hepatic Neutral Diarrhea and abdominal Decrease in both
glucose production, discomfort; lactic acidosis microvascular and
increase insulin (rare); contraindicated in macrovascular events
mediated uptake of presence of progressive
glucose in muscles liver, kidney or cardiac
failure
a-Glucosidase inhibitors Inhibit polysaccharide Neutral Flatulence; abdominal May reduce CVD events
(acarbose, miglitol, absorption discomfort
voglibose)b
DPP-4 inhibitors Slow gastric emptying, Neutral Hypoglycemia when used No increase in ischemic
(sitagliptin, saxagliptin, suppress glucagon in combination with cardiovascular events;
vildagliptin, linagliptin, secretion sulfonylureas; nausea; increased rate of
alogliptin)b increased risk of infections; hospitalization for heart
possible increased risk of failure with saxagliptin
pancreatitis
SGLT2 inhibitors Increases kidney Decrease Hypoglycemia with insulin None
(dapagliflozin and excretion of glucose secretagogues and insulin;
canagliflozin)b hypotension; kidney
impairment; hypersensitivity
reactions; increased
candidal genital infections
and urinary tract infections
CVD = cardiovascular disease; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; SGLT2 = sodium-glucose co-transporter 2.
11lnjection.
bQral.
10
Disorders of Glucose Metabolism
candidates to consider. Weight gain is likely with the use of and severe hyperglycemia that can lead to volume depletion
insulin, sulfonylureas, thiazolidinediones, and meglitinides. and electrolyte abnormalities.
The risk of hypoglycemia must be considered with the selec
tion of any therapeutic agent, particularly when it is com Hospitalized Patients with Diabetes Mellitus
bined with insulin secretagogues or insulin. Gastrointestinal Critically ill patients with type l diabetes mellitus will require
side effects from GLP-1 mimetics and pramlintide may insulin therapy upon admission to the hospital. For critically
decrease tolerability for some patients and should not be ill patients with type 2 diabetes, intravenous insulin infusion
used in patients with gastroparesis. Patients with frequent therapy should be initiated when plasma glucose levels exceed
candidal genital infections would not be ideal candidates for 180 to 200 mg/dL (10-11.l mmol/L). Glucose goals on intrave
SGLT2 inhibitor therapy. nous insulin are 140 to 200 mg/dL (7.8-11.1 mmol/L) with
Insulin therapy should be strongly considered in the set frequent bedside point-of-care (POC) monitoring every 1 to
ting of symptomatic hyperglycemia or markedly elevated 2 hours for insulin adjustments.
hemoglobin A,c (>8.5% to 9%) at the time of diagnosis or In noncritically ill patients, the ADA and AACE advocate a
when lifestyle modifications and/or noninsulin therapies fail premeal glucose goal of less than 140 mg/ell (7.8 mmol/L)
to achieve glycemic goals. The American Association of and random plasma glucose values less than 180 mg/clL
Clinical Endocrinologists (AACE) recommends weight-based (10 mmol/L). Therapy adjustments should be considered when
initiation of basal insulin at initial doses of 0.1 to 0.3 U/kg. plasma glucose levels are less than 100 mg/dL (5.6 mmol/L)
The dose should be increased several units every 2 to 3 days and are necessary when glucose values fall below 70 mg/dL
to reach fasting plasma glucose goals, based on the patient's (3.9 mmol/L) to avoid continued hypoglycemia. In contrast. the
SMBG readings. Reductions of insulin doses by 10% to 40% American College of Physicians (ACP) recommends avoiding
should be made in the setting of hypoglycemia with insulin glucose levels less than 140 mg/dL (7.8 mmol/L) owing to the
titrations. If glycemic goals are not met with basal insulin, increased risk of hypoglycemia with tighter glycemic control.
then prandial insulin should be added to the regimen with Insulin is the preferred therapy and likely the safest choice
frequent titration of doses for optimal glucose control. When for achieving inpatient glycemic control. Use of sliding scale
premeal glucose values are not at a patient-specific goal, the insulin alone is not recommended, as it is not physiologic and
preceding prandial insulin dose should be increased or frequently causes large glucose fluctuations owing to the
decreased by 10% to 20% in the setting of hyper- or hypogly inherent reactive nature of its dosing, coupled with the near
cemia, respectively. (Also see section on Therapy for Type 1 universal lag time between measurement of glucose and injec
Diabetes Mellitus.) tion of insulin that occurs in most hospitals. The recom
mended insulin regimen should incorporate both basal and
KEY POINTS
prandiaJ coverage. In the setting of preprandial hyperglycemia.
• For patients with type 2 diabetes mellitus, metformin is pranclial coverage can be supplemented with additional insu
recommended first-line therapy and should be initiated lin (correction factor insulin). Prandial coverage should
in conjunction with lifestyle modifications; it has a account for the carbohydrates consumed at each meal and be
lower incidence of hypoglycemia and weight gain com adjusted accordingly. POC glucose monitoring should coincide
pared with some of the other oral agents and insulin. with insulin administration before meals and at bedtime. with
• In older patients with type 2 diabetes mellitus of longer overnight measurements to monitor for hypoglycemia only if
disease duration, treatment of severe recurrent hypo fasting readings are elevated or the patient is symptomatic.
glycemia should take precedence over controlling This glucose monitoring regimen will simulate the patient's
hemoglobin A,c values; the increased risks of hypogly home routine after discharge. POC monitoring should occur
cemia outweigh the risks of diabetes complications. every 6 hours when a patient is on insulin therapy and receives
nothing by mouth.
Outpatient CSII therapy can be continued if the patient is
CJ Inpatient Management physically and mentally able to safely administer this therapy
under proper supervision from health care providers with CS!I
of Hyperglycemia expertise. POC glucose monitoring, basal rates of insulin, and
Inpatient hyperglycemia, defined as consistently elevated patient-initiated bolus amounts of insulin should be docu
plasma glucose values above 140 mg/dL (7.8 mmol/L). is asso mented in the medical record.
ciated with poor outcomes. Attempts lo decrease morbidity Oral agents and noninsulin injectable agents do not have
and mortality with tight glycemic control (80-110 mg/dL [4.4- safety or efficacy data in the hospital setting. The safest recom
6.l mrnol/L]) have not consistently demonstrated improve mendation is to discontinue these agents upon admission to the
ments in adverse outcomes and, in some settings, have shown hospital. although continuation can be considered in a stable
increased rates of severe hypoglycemic events and mortality. patient with glycemic control at goal and no anticipated changes
As a result, revised inpatient glycemic targets are less stringent in nutrition or hemodynamic status. These agents can be par
than outpatient glucose targets to avoid both hypoglycemia ticularly dangerous in fasting states or when organ pe1fusion or
11
Disorders of Glucose Metabolism
r,,, !'unction is compromised. Resumption of these medications corrected. cognitive function begins to decline and can be
LIi.i may be considered once a patient is stable with regular activities rapidly followed by loss of consciousness. seizures. and
and nutrition or at the time of hospital discharge. Cl
CONT.
death. Relative hypoglycemia occurs when a patient has
symptoms of hypoglycemia but the plasma glucose level is
KEY POINTS
greater than 70 mg/dL (3.9 mmol/L). This can occur with
• For critically ill patients with type 2 diabetes mellitus, rapid decreases in glucose or with correction of glucose to
intravenous insulin infusion therapy should be initiated near-normal glycemic levels in a patient with a history of
when plasma glucose levels exceed 180 to 200 mg/dL prolonged hyperglycemia (plasma glucose >200 mg/dL
(10-11.1 mmol/L); glucose goals on intravenous insu [11.1 mmol/L]). Relative hypoglycemia can be diminished if'
lin are 140 to 200 mg/dL (7.8-11.1 mmol/L) with fre glucose levels are maintained closer to normal ranges and if
quent bedside point-of -care monitoring every 1 to treatment to goal glucose level is achieved over a longer
2 hours. period of lime in patients with a history of prolonged uncon
H'IC • For noncritically ill patients, basal and prandial subcu- trolled diabetes.
taneous insulin is the preferred and safest choice for The etiology of hypoglycemia can be quite variable.
achieving inpatient glycemic; oral agents and noninsu Exercise can lead to hypoglycemia if appropriate measures
lin injectable agents do not have proven safety or effi are not taken to avoid it. Prior to exercise. consumption of a
cacy data in the hospital setting. snack with 15 to 30 g of carbohydrates can help reduce the
risk of hypoglycemia. or a patient can reduce the close of
Hospitalized Patients Without Diabetes Mellitus prandial insulin given at the meal prior to the planned exer
cise. if on an MDI regimen. A snack with complex carbohy
Hyperglycemia as a result of acute stress relalecl to illness.
drates is often required after prolonged exercise lo replenish
concomitant medications. or enteral/parenteral nutrition can
glycogen stores since glucose utilization can be prolonged in
occur in patients without a previous history of glucose abnor
muscles and the liver. In over weight/obese patients.
malities. The glycemic goals and glucose-management strate
decreasing the insulin close instead of ingesting snacks
gies in Lhis population should follow those for hospilalized
before exercise can avoid additional weight gain. Poor tim
patients with diabetes. Hyperglycemia in hospitalized patients
ing or skipping of meals or consumption of smaller amounts
may also indicate the presence of previously undiagnosed
of' food without an adjustment to insulin doses or oral hypo
diabetes. Measurement of hemoglobin A1 , in hyperglycemic
glycemic agents can cause hypoglycemia. Use of a non
non-hospilalizecl patients, if feasible, can provide insight into
physiologic sliding scale insulin regimen or use of an
the length of the hyperglycemia. A hemoglobin A1c level
aggressive supplemental insulin correction factor regimen
greater lhan 6.5% suggests long-standing hyperglycemia.
is often the etiology of hypoglycemic events. A reduction in
Follow-up diabetes screening and care should be implemented
kidney function. particularly in elderly patients, can
after discharge from the hospital.
decrease clearance of insulin or insulin secretagogues and
lead to prolonged hypoglycemia. Alcohol consumption can
cause delayed hypoglycemia.
Management of Hypoglycemia Treatment of hypoglycemia is twofold: immediate cor
Hypoglycemia in Patients with Diabetes Mellitus rection of hypoglycemia and prevention of future events. If' a
Hypoglycemia is a common complication of intensive thera patient is conscious. 15 to 20 g of a carbohydrate with glucose
peutic regimens in patients with diabetes mellitus, often limit should be consumed. Glucose tablets or glucose gel are ideal
ing the ability to safely reach glycemic goals for many patients. treatment regimens. The blood glucose level should be
Avoidance of hypoglycemia prior to focusing on a patient's checked again after 15 minutes. and consumption of 15 to
hemoglobin A 1 , goal is of utmost importance because of the 20 g of glucose should occur again if the hypoglycemia does
significant morbidity and mortality associated with low not improve to greater than 70 mg/dL (3.9 mmol/L). Since the
plasma glucose levels. eftects of the insulin or oral hypoglycemic agents are likely
Hypoglycemia is defined as a plasma glucose level less still present, a meal or snack should be consumed after the
than 70 mg/ell (3.9 rnrnol/U. Insulin secretion ceases when glucose has been corrected to avoid continued hypoglycemia.
the glucose level falls below 80 mg/ell (4.4 mmol/L). Every patient with diabetes on medications associated with
Hyperaclrenergic symptoms begin to alert the patient to hypoglycemia should receive a prescription for a glucagon kit,
hypoglycemia Lhrough an increase in heart rate. swealing. which should be used when oral consumption of glucose is
lremors. hunger. and anxiety when glucose levels decline. not possible or safe.
Typically. Lhe body responds to hypoglycemia by secreting Relaxing the glycemic targets and hemoglobin A 1 , goals
cou nlerregulatory hormones. such as glucagon, epinephrine, and reducing doses of therapeutic agents will decrease the risk
norepinephrine. cortisol. and growth hormone. in succes of future hypoglycemia. A review of a patient's diabetes self-
sion based on the escalating degree of hypoglycemia. lf the management skills can also help identify recurring risk factors
counterregulatory measures fai I or the hypoglycemia is not for hypoglycemia. Cl
12
Disorders of Gluc o s e Metabolism
'Symptomatic hypoglycemia, fasting plasma glucose 55 mg/dl (3.1 mmol/L) or lower, and prompt symptomatic relief with correction of hypoglycemia (Whipple triad).
Data from Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin
Endocrinol Metab. 2009 Mar:94(3):709-28. [PMID: 19088155[
13
Disorders of Glucose Metabolism
Cl
COiT.
mc,ils composed olprotcin. l�ll. and ccirbohydr<1te to avoid the
sensation of' hypoglycemia.
ketone laboratory measurements often use the nitroprusside
reaction, which only estimates acetoacetate and acetone lev
els that may not be elevated initially. Although hyperglyce
mia is the typical f1nding <11 presentation with DKA. patients
Acute Complications of can present with a range of'plasma glucose values. including
those in the normal range (Figure I). The anion gap is ele
Diabetes Mellitus vated. Stress-related mild leukocytosis is of'len present.
Diabetic Ketoacidosis and Hyperglycemic Higher levels of leukocytosis may indicate an infectious pro
Hyperosmolar Syndrome cess as the etiology of' the hyperglycemia. Serum sodium
Diabetic ketoacidosis (OKA) and hyperglycemic hyperosmo levels can be low clue to osmotic shifts of' water f'rom the
IJ r syndromc (I I HS) Jre ,1cute compI ications of' uncontrolled intracellular to extracellular spaces. Normal or elevated
hyperglycemia with life-threatening consequences ii. not serum sodium levels are indicative of severe volume deple
recognized and treated early. DKA typically occurs in the tion. Serum potassium levels may be elevated due to shifts
setting of' hyperglycemia with relative or absolute insulin from the intracellular to extracellular spaces due to ketoaci
clef'iciency ,rncl <111 increase i 11 counterregu latory hormones. dosis and the absence of suf'fkienl insulin. Normal or low
Suf'f'icient amounts or insulin are not present to suppress potassium levels on presentation indicate low potassium
lipolysis and oxid,1tion of' f'ree fatty acids. which results in stores in the body with need for correction prior to initiation
ketone body production and subsequent metabolic acidosis. of' insulin therapy to avoid cardiac arrhythmias. Serum amyl
l)Ki\ occurs more f'requently with type I diabetes. although ase and lipase levels also can be elevated in the absence of
10'':, to 30% of' cases occur in patients with type 2 diabetes. p,rncreatitis.
111 IS occurs in the setting of'parlial insulin def'iciency that is HHS typically presents with normal or small amounts
more typical of' type 2 diabetes. There is sufficient insulin in of'urine or serum ketones. Plasma glucose values in HHS are
patients with HHS to suppress lipolysis and production of' typically greater than in OKA and can exceed 1200 mg/ell
ketone bodies. but inadequate amounts to prevent the (66.6 mmoltU. The serum osmolality is elevated greater
hyperglycemia. dehydration. and hyperosmolality charac than 320 mOsm/kg H 2 0. The serum bicarbonate level is
teristic of' HHS. greater than 18 mEq/L (JS mmol/L.). and the pH remains
Se\·eral risk factors Gm precipitate the development or greater than 7.3.
extreme hyperglycemia: infection. intentional or inadvertent Treatment of OKA and HHS requires correction of hyper
insulin therapy nonadhercnce. myocardial inforction. stress. glycemia with intravenous insulin infusions. f'requent moni
trauma. <llld confounding medications. such as glucocorti toring and replacement of electrolytes. correction of hypov
coids or ,llypical antipsychotic agents. In addition. DKA may olemia with intravenous fluids. and possible correction of'
be the initial clinical presentation in some patients with previ acidosis (Table 11). The ICU is the best place for management
ously undiagnosed type I or type 2 diabetes. An illness or event of severe hyperglycemia because of the frequent monitoring
that leads to dehydration will of'tcn precipitate the hyperglyce required with intravenous insulin therapy. the need for mon
mia associated with HI IS. itoring for potential electrolyte-induced arrhythmias. and the
Symptoms of' extreme hyperglycemia in Dl(A and HHS potential for rapid decompensation. Plasma glucose levels
include polyuria. polydipsia. unintentional weight loss. vomit should be monitored initially every hour while on insulin
ing. weakness. and mentation changes. Dehydration and met infusion therapy. Electrolytes should be monitored every 2 to
abolic abnormalities worsen as hyperglycemia progresses. 4 hours. depending on the initial electrolyte deficits and level
which can lead to respiratory failure. lethargy. obtundalion. of' acidosis. Cl
coma. and death. OKA can occur within several hours of the
KEY POINTS
inciting event. The development of HHS is less acute than OKA
and may take dJys to weeks lo develop. HHS typically presents • The development of hyperglycemic hyperosmolar syn
with more extreme hyperglycemia and mental status changes drome is less acute than that of diabetic ketoacidosis
compared with OKA. and may take days to weeks to develop; however, hyper
The initi.11 e\·,duation of'severe hyperglycemi;i includes glycemic hyperosmolar syndrome typically presents
�erologic studies (plasma glucose. serum ketones. blood with more extreme hyperglycemia and mental status
urea nitrogen. creatinine. electrolytes. calculated anion changes compared with diabetic ketoacidosis.
gap. arterial blood gases. osmolality. complete blood count • Treatment of diabetic ketoacidosis and hyperglycemic
with differential. blood cultures). urine studies (ketones. hyperosmolar syndrome requires correction of hyper
urinalysis. urine culture). chest radiograph. and an elec glycemia with intravenous insulin infusions, frequent
trocardiogram. monitoring and replacement of electro'lytes, correction
Urine ancl serum ketones are elevated in DKA: however. of hypovolemia with intravenous fluids, and possible
a negative measurement initially does not exclude OKA. correction of acidosis.
�-Hydroxybutyrate is the major ketone body in OKA. but
14
Disorders of Glucose Metabolism
28
Hyperosmolar
26 Normal Nonketotic
Range
24
22
20
18
16
:.c 14
E
12
Ill
10
8
Classic
6 Euglycemic
OKA
4
0
100 200 300 400 500 600 700 800 900 1000
5.6 11.1 16.7 22.2 27.8 33.3 38.9 44.4 50.0 55.5
Plasma glucose (mg/dl [mmol/L))
FIGURE 1. Spectrum of metabolic decompensation that occurs in diabetic ketoacidosis. DKA = diabetic ketoacidosis.
Assess for volume status, then Give regular insulin, 0.1 U/kg, as Assess for adequate kidney If pH is <6.9, give sodium
give 0.9% saline at 1 Uh initially an intravenous bolus followed function, with adequate urine bicarbonate, 100 mmol in
in all patients, and continue if by 0.1 U/kg/h as an intravenous output(approximately 50 400 ml of water, and
patient is severely hypovolemic. infusion; if the plasma glucose mUh). If serum potassium is potassium chloride, 20 mEq,
Switch to 0.45% normal saline level does not decrease by <3.3 mEq/L(3.3 mmol/L), do infused over 2 hours. If pH is
at 250-500 mUh if corrected 10% in the first hour, give an not start insulin but instead 6.9 or greater, do not give
serum sodium level becomes additional bolus of 0.14 U/kg give intravenous potassium sodium bicarbonate.
normal or high. When the and resume previous infusion chloride, 20-30 mEq/h, through
plasma glucose level reaches rate; when the plasma glucose a central line catheter until the
200 mg/dl(11.1 mmol/L) in level reaches 200 mg/dl(11.1 serum potassium level is
patients with DKA or 300 mg/ mmol/L) in DKA and 300 mg/dl >3.3 mEq/L(3.3 mmol/L); then
dL(16.7 mmol/L) in HHS, switch (16.7 mmol/L) in HHS, reduce to add 20-30 mEq of potassium
to 5% dextrose with 0.45% 0.02-0.05 U/kg/h, and maintain chloride to each liter of
normal saline at 150-250 mUh. the plasma glucose level intravenous fluids to keep the
between 150-200 mg/dl serum potassium level in the
(8.3-11.1 mmol/L) until anion 4.0-5.0 mEq/L(4.0-5.0 mmol/L)
gap acidosis is resolved in DKA. range. If the serum potassium
level is >5.2 mEq/L(S.2 mmol/L),
do not give potassium chloride
but instead start insulin and
intravenous fluids and check
the serum potassium level
every 2 hours.
15
Diso rder s of Gluco se Metabolism
hThe American Diabetes Association guidelines state that it is reasonable to assess progression of disease and response to therapeutic interventions with continued monitoring of
urine albumin excretion.
16
Disorders of Glucose Metabolism
17
Disorders of the Pituitary Gland
prevent the development of neuropathy, and sustained optimal tions, pain, ankle reflexes, and foot deformities. Patients
glucose levels can delay the progression of neuropathy. should inspect their feet daily for early detection of any abnor
Distal symmetric polyneuropathy (DPN) is the most mality and wear appropriate footwear. Although patients with
common form of diabetic neuropathy. It is characterized by a diabetes have different footwear needs, the selection of shoes
"stocking-glove" distribution that ascends proximally. DPN should take into account several important factors: intended
frequently presents as a sensation of numbness, tingling, use, plantar protection, shape and fit on the foot, and stability
burning, heaviness, pain, or sensitivity to light touch. The issues (see MKSAP 17 Infectious Disease).
pain may worsen at night and with walking. Muscle weakness
may occur in severe cases. DPN is a risk factor for muscle and Hypoglycemic Unawareness
joint deformities, such as Charcot foot, and foot ulcers. DPN Frequent severe hypoglycemia can diminish the ability to
evaluation includes assessment of ankle reflexes, vibration detect life-threatening hypoglycemia. This unawareness is
sensation with a 128-Hz tuning fork, and touch with a 10-g caused by failure of the release of counterregulatory hormones
monofilament and pinprick. Screening intervals are found in to trigger an autonomic response to decreased glucose levels.
Table 12. Management of DPN symptoms may require one or Continual avoidance of hypoglycemia for several weeks or
more classes of drugs, including antidepressants (amitripty longer may help restore the body's ability to detect hypoglyce
line, venlafaxine, duloxetine, paroxetine), anticonvulsants mia. Plasma glucose levels should be kept greater than 150 mg/
(pregabalin, gabapentin, valproate), or capsaicin cream. dL (8.3 mmol/L) during the time period when restoration of
Autonomic neuropathy can affect a single organ or multi hypoglycemic symptoms is the goal to avoid unintended and
ple organs. Symptoms may include gastroparesis, diarrhea, unexpected hypoglycemia. Continuous glucose monitoring
constipation, neurogenic bladder, abnormal hidrosis, and systems can be useful for hypoglycemia management by alert
erectile dysfunction. Cardiac symptoms include resting sinus ing the patient to rapid decreases in glucose levels to allow
tachycardia, orthostatic or postprandial hypotension, exercise prompt correction and avoidance of hypoglycemia (see Self
intolerance, and silent myocardial infarction. Cardiovascular Monitoring of Blood Glucose).
autonomic neuropathy is an independent risk factor for mor
KEY POINT
tality, which underscores the need to reduce other cardiovas
cular risk factors in these patients. • Distal symmetric polyneuropathy (DPN) is the most com
Diabetic amyotrophy occurs in older patients or those mon form of diabetic neuropathy, and it presents as a sen
with type 2 diabetes, and may be due to infarcts in the major sation of numbness or burning pain in a stocking-glove
nerve trunks of the leg. It can present acutely with severe pain distribution; management may require one or more
and asymmetric proximal weakness or pain in the leg, weight classes of drugs, including antidepressants (amitriptyline,
loss, and autonomic neuropathy. Partial remission may occur venlafaxine, duloxetine, paroxetine), anticonvulsants
over many months. Without any approved treatments for dia (pregabalin, gabapentin, valproate), or capsaicin cream
betic amyotrophy, management consists of symptomatic ther
apy for neuropathic pain and ambulatory aids, if necessary.
Mononeuropathies can occur acutely with a cranial or Disorders of the
peripheral distribution. There are no specific treatments for
these mononeuropathies, as the symptoms usual resolve Pituitary Gland
within a few months. Nerve compression syndromes, such as Hypothalamic and Pituitary
carpal tunnel syndrome or peroneal palsy, occur frequently in
patients with diabetes. See MKSAP 17 Neurology for more Anatomy and Physiology
information regarding diabetic neuropathy. Referral to a neurolo The anterior pituitary is made up of glandular tissue that
gist for electrodiagnostic testing or evaluation for nondiabetic receives its blood supply from the hypothalamus through the
related etiologies should occur with severe, rapidly progressive, hypothalamic-pituitary portal plexus, whereas the posterior
or atypical neuropathies. pituitary consists of direct extension of neurons from the
hypothalamus. Both the portal blood system and the hypo
Diabetic Foot Ulcers thalamic neurons transverse from the hypothalamus to the
Diabetic foot ulcers increase the risk for amputation and subse pituitary by way of the pituitary stalk. The hypothalamus
quent morbidity and disability. The etiology is often multifacto regulates anterior pituitary gland function by synthesizing
rial. Loss of peripheral sensation can result in significant injuries specific stimulating and inhibiting hormones, which are
that may be undetected by the patient. Peripheral arterial disease released in the portal blood. Posterior pituitary hormones are
predisposes to the development of lower extremity ischemic synthesized in the hypothalamus and travel through hypotha
ulcers and impairs healing. Altered leukocyte function from lamic neurons to be secreted by the posterior pituitary gland.
hyperglycemia can impede wound healing of injuries. The anterior and posterior lobes are joined by the Rathke
Clinicians should evaluate the feet at least annually to pouch. Table 13 lists the pituitary hormones and initial testing
assess for pedal pulses, sensation, ulcers, skin or nail infec- for suspected pituitary hormone excess or deficiency.
18
Disorder s of the Pituitar y Gland
TABLE 13. Initial Testing for Pituitary Hormone Deficiency and Excess
Pituitary Hormone Excess
Pituitary Hormone Peripheral Hormone Initial Test(s)
GH IGF-1 IGF-1
TSH Thyroxine, TSH, free (or total) thyroxine
triiodothyronine
ADH ADH Simultaneous serum sodium, urine and serum osmolality Water deprivation test
LH and FSH b
Sex hormones Simultaneous LH, FSH, testosterone (male), estriol (female)
TSH Thyroxine, Simultaneous TSH, free (or total) thyroxine
triiodothyronine
ACTH = adrenocorticotropic hormone; AOH = antidiuretic hormone; FSH "" follicle -stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1;
LH = luteinizing hormone; TSH = thyroid-stimulating hormone.
asee Table 15 for additional information on confirmatory testing for pituitary dysfunction.
bRoutine testing for deficiency is not recommended without specific signs of deficiency such as amenorrhea, gynecomastia, or impotence.
The anterior pituitary gland secretes and releases six hor gonadotropin-releasing hormone (GnRH). LH and FSH regu
mones: adrenocorticotropic hormone (ACTH), thyroid-stimu late normal male and female reproductive function. GH pro
lating hormone (TSH), the gonadotropins-luteinizing duction is regulated by somatostatin. Prolactin controls
hormone (LH) and follicle-stimulating hormone (FSH), lactation and is inhibited by dopamine.
growth hormone (GH), and prolactin. ACTH is released in The posterior pituitary gland secretes oxytocin, which is
response to corticotrophin-releasing hormone (CRH) and acts necessary for parturition, and antidiuretic hormone (ADH,
on the adrenal glands to promote the synthesis and secretion also called vasopressin), which regulates water balance.
of cortisol. TSH is released in response to thyrotropin-releas The pituitary gland is posterior and superior to the sphe
ing hormone (TRH) and acts on the thyroid to stimulate thy noid sinus, which provides surgical access to the gland, and is
roid hormone production. LH and FSH are differentially adjacent to the optic chiasm, the carotid arteries, and the cav
released from the pituitary gland in response to pulses of ernous sinuses (Figure 2).
FIGURE 2. A coronal MRI (left) and sagittal MRI (right) showing the pituitary gland (open arrow), pituitary stalk (thin arrow), optic chiasm (arrowhead), sphenoid sinus
(star), and carotid artery (curved arrow).
19
Disorders of the Pituitary Gland
The pituitary gland is best imaged using MRI with gado Pituitary tumors are almost always nonmalignant. Two
linium. Because the normal pituitaty is relatively small, a exceptions are metastatic disease and the very rare pituita1y
dedicated pituitary protocol that obtains thin MRI slices carcinoma. Additional kinds of noncancerous pituitary lesions
through the sella is used. include craniopharyngiomas, meningiomas, and Rathke cleft
cysts. Inflammatory and infiltrative disorders, including lym
phocytic hypophysitis, sarcoidosis, hemochromatosis, amyloi
Pituitary Tumors dosis, L angerhans cell histiocytosis, lymphoma, and
Pituitaiy adenomas, which are benign, are the most common tuberculosis, can affect the pituitary gland.
tumor of the pituitary gland. A tumor less than 1 cm is defined Lymphocytic hypophysitis is an inflammatmy pituitary
as a microadenoma, and a tumor 1 cm or larger is termed a lymphocytic infiltration that most commonly occurs in preg
macroadenoma (Figure 3). Pituitary adenomas are common. nant and postpartum women. It may cause transient or per
Autopsy studies document that 10% of the general population manent pituitary insufficiency. Lymphocytic hypophysitis is
had undiagnosed pituitary adenomas. Frequently, pituitary treated with glucocorticoids.
adenomas are incidental findings on imaging studies completed A sellar mass can compress normal surrounding tissue
for other reasons. When patients undergo brain MRI, 10% to and impair normal neurologic and pituitaty function. Pituitary
38% are found to have incidental pituita1y microadenomas and adenomas may also be functional and secrete excess hormone.
0.2% have incidental pituitaiy macroadenomas. Certain genetic
mutations increase the chance of developing a pituitary tumor. Incidentally Noted Pituitary Masses
When J pituitary tumor is incidentally noted. investigation CJ
Approach to a Sellar Mass must determine (!) whether it is causing a mass effect. (2)
When a sellar mass is noted, pituitary adenomas are most \\'hether it is secreting excess hormones. and (.3) whether it has
likely; however, they need to be distinguished from other a propensity to grow and cause problems in the ruture. After a
pituita1y lesions and nonpathologic pituitary enlargement. thorough history and physical cxa111ination. bioche111ical test
The pituitary gland is enlarged diffusely in untreated pri ing can be undertaken in a targeted fashion based on the
mary hypothyroidism and during pregnancy. When possible, 1x11icn1·s clinical signs and symptoms. Initial tests could include
imaging of the pituitary gland should be avoided or delayed in me;1surement or 8 .\,! cortisol. TSH. f'ree (or tot,11) thyroxine
pregnancy and in untreated primary hypothyroidism because Cl). prolactin. and insulin like growth factor J (IGF \).
gland enlargement on imaging may prompt an expensive and II the tu111or is not causing mass effect and there is no
unnecessa1y evaluation for pituita1y hormone abnormality C\'idence of' hor111onc excess. a pituitary MRI should be
and tumor. rcpc�1tecl in 6 111onths frir a macroadenoma ,rnd 12 months for
FIGURE 3. A coronal MRI (left) and sagittal MRI (right) showing a large pituitary macroadenoma. The normal pituitary gland and the optic chiasm cannot be seen because
of compression from the tumor. The tumor is invasive into the left cavernous sinus. Likely, the tumor appears heterogeneous because of internal necrosis.
20
Disorders of the Pituitary Gland
CJ a microadenoma to assess for growth. If no growth occurs. tumor may cause minimal peripheral vision loss, bilemporal
MR ls should be repeated every I to 2 years for the next 3 years hemianopsia. or complete blindness. Visual field testing is a
CONT.
and then intermittently thereafter. In a patient at risk for can- sensitive measure of optic nerve damage and should be evalu
cer or with a histo1y of cancer. metastatic disease must be ated by an ophthalmologist in patients who report a change in
excluded. Cl vision. who have a pituitary t·umor that abuts or compresses
the chiasrn on MRI. or who have any evidence of gross periph
Empty Sella eral vision loss on physical examination. Change in vision due
Empty sella is diagnosed when the normal pituitary gland is lo optic chiasm compression is an indication for treating a
not visualized or is excessively small on MRI; it is a radiologic pituitary tumor.
finding and not a distinct clinical condition. The pituitary sella Pituitary tumors can also invade surrounding brain tissue
is said to be "empty" because normal tissue is not seen. The leading to seizures and neurologic manifestations. Pituitary
finding may be primarily due to increased cerebrospinal fluid tumors can invade the cavernous sinus. causing damage to
entering and enlarging the sella, or it may be secondary to a cranial nerves Ill, IV. and VJ that pass through the sinus caus
tumor, previous pituitary surgery, radiation, or infarction. ing diplopia and extraocular muscle palsies/paralysis. Cl
Empty sella can also occur as a congenital abnormality when
KEY POINT
the sella is normal size, but the pituitary is small. When empty
sella is found incidentally on imaging, an evaluation should be • Pituitary masses can compress the normal pituitary
completed to determine if there is a known cause for second gland, causing hormone deficiencies; a large pituitary
ary empty sella and if the patient has signs or symptoms of mass may cause panhypopituitarism in which there is
pituitary hormone deficiency. A patient without signs or impaired secretion of all pituitary hormones.
symptoms should be screened for cortisol deficiency and
hypothyroidism with 8 AM cortisol, TSH, and free (or total) T4. Treatment of Clinically Nonfunctioning
A patient with signs of pituitary hormone deficiency should Pituitary Tumors
receive a more complete biochemical evaluation of the pitui Nonfunctioning pituitary tumors that are growing or causing
tary axes, based on the signs and symptoms found. mass effect are treated with neurosurgery. The most common
Repeat imaging is not necessary unless indicated as sur surgical approach is transsphenoidal through the nares or the
veillance for the underlying pathology that resulted in the mouth. A very large or invasive tumor may require craniotomy
empty sella. for decompression. Indications for surgery include mass effect,
particularly a visual field defect; tumor that abuts the optic
KEY POINTS
chiasm; tumor growth; or an invasive tumor (invading the
• Incidentally noted pituitary tumors are common, and brain or cavernous sinus). Surgery should also be considered
biochemical testing is informed by findings on history in a patient with a tumor close to the optic chiasm who plans
and physical examination. to become pregnant (due to the physiologic enlargement of the
• Initial tests for pituitary incidentally noted masses pituitary associated with pregnancy).
include measurement of 8 AM cortisol, thyroid-stimulat Functional pituitary tumors will be discussed later in this
ing hormone, free (or total) thyroxine (T4), prolactin, chapter, based on the hormone in excess (see Pituitary
and insulin-like growth factor 1. Hormone Excess).
• Empty sella is diagnosed when the normal pituitary KEY POINT
gland is not visualized or is excessively small on MRI;
• Nonfunctioning pituitary tumors that are growing or
it is a radiologic finding and not a distinct clinical
causing mass effect are treated with neurosurgery.
condition.
21
Disorders of the Pituitary Gland
22
Disorders of the Pituitary Gland
ACTH (cortisol) ACTH stimulation Measure baseline serum cortisol level. Serum cortisol level >18 µg/dl(496.8 nmol/L)
deficiency test Administer 250 µg of synthetic ACTH. indicates a normal response.
Measure cortisol levels at 30 and 60 minutes.
ADH deficiency Water deprivation Patient empties bladder, and baseline Water deprivation test interpretation:
(DI) test, followed by weight is measured. Measure urine volume
desmopressin and osmolality hourly. Measure serum Urine osmolality >600 mOsm/kg H 2 0 is a
challenge if sodium, osmolality, and weight every normal response to water deprivation,
indicated 2 hours. indicating ADH production and peripheral
effect are intact.
The test is stopped when one of the Urine osmolality <600 mOsm/kg H 2 0, serum
following occurs: osmolality >295 mOsm/kg H 2 0 and/or serum
sodium >145 mEq/L(145 mmol/L) are
Urine osmolality exceeds 600 mOsm/kg diagnostic of DI.
H 20
Patient has lost 5% of body weight
Desmopressin challenge interpretation:
Urine osmolality is stable for 2-3 h while
serum osmolality rises >100% increase in urine osmolality is
diagnostic of complete central DI.
- Plasma osmolality >295 mOsm/kg H 20
0% increase in urine osmolality is diagnostic of
- Serum sodium >145 mEq/L(145 mmol/L) complete nephrogenic DI.
Desmopressin challenge if final urine >50% increase in urine osmolality is
osmolality <600 mOsm/kg H 2 0, serum diagnostic of partial central DI.
osmolality >295 mOsm/kg H 2 0, or serum
sodium >145 mEq/L(145 mmol/L): <50% increase in urine osmolality is
diagnostic of partial nephrogenic DI.
Give desmopressin 1 µg subcutaneously.
Measure urine osmolality every 30 minutes
for 2 hours.
Growth Glucose 75 g oral glucose tolerance test. Measure GH <0.2 ng/ml(0.2 µg/L)is a normal response.
hormone excess tolerance test glucose and GH at 0, 30, 60, 90, 120, and GH 2'1.0 ng/ml(1.0 µg/L)(or 2'0.3 ng/ml
(acromegaly) 150 minutes. [0.3 µg/L] on an ultrasensitive assay) is
diagnostic of acromegaly.
ACTH = adrenocorticotropic hormone; ADH = antidiuretic hormone; DI = diabetes insipidus; GH = growth hormone.
Cl greater than 20 µg/dL (552 nrnol/L). When the test result is physiologic stress (major surgery, trauma. critical illness, or
normal, patients no longer require daily cortisol replacement. childbirth). hydrocortisone (150-200 mg/d intravenously in
CONT.
but should follow "sick day rules" (increasing cortisol replace- 3-4 divided doses; 100 mg/d the next day; taper to baseline in
ment dose during illness) for up to a year after cessation of 3-5 days) may be used. An alternative would be dexametha
daily cortisol replacement. sone (6-8 mg/cl intravenously in 2-3 divided closes). If the
Symptoms of secondary cortisol deficiency include patient has pituitary apoplexy and urgent/emergent neuro
weight loss, nausea. vomiting. lightheadedness, hypoglyce surgery is planned with no time for ACTH-stimulation test
mia. hypotension, and hyponatremia. Secondary cortisol defi ing. the patient should empirically be treated with glucocor
ciency is also diagnosed using an ACTH stimulation test. ticoicls and then receive an ACTH stimulation test 4 to 8 weeks
Secondary cortisol deficiency can be life threatening and must after surgery. Cl
be treated with glucocorticoid replacement. often with hydro
cortisone. although prednisone or dexamethasone may also be Thyroid-Stimulating Hormone Deficiency
used. Hydrocortisone (15-30 mg/d) should be administered in Thyroid-stimulating hormone (TSH) deficiency leads to sec
2 to 3 cliviclecl doses. or hydrocortisone should be dosed 10 to ondary or central hypothyroidism. Secondary hypothyroidism
20 mg in the morning and 5 to 10 mg in the early afternoon. is clinically identical to primary hypothyroidism (see Disorders
Patients require stress doses of glucocorticoids when of the Thyroid Gland).
acutely ill. hospitalized, or undergoing the stress of' surgery. Secondary hypothyroidism is diagnosed by demonstrating
For moderate physiologic stress (minor or moderate surgery a simultaneously inappropriately normal or low TSH and low
with general anesthesia), hydrocortisone should used (45- T4 (free or total). Patients are treated with levothyroxine
75 mg/d orally or intravenously in 3-4 divided doses for replacement in the same manner as primary hypothyroidism;
2-3 days). Prednisone (10-20 mg or dexamethasone 2-3 mg/d however, the serum TSH cannot be used to monitor and assess
in 1-2 divided doses) may be used alternatively. For major for adequacy of thyroid hormone replacement dosing. Instead,
23
Disorders of the Pituitary Gland
the levothyroxine dose is adjusted based on free T4 levels with isolated adult-onset GH deficiency is extremely rare, and its
the goal of obtaining a value within the normal reference range. clinical significance in adults is debated. Therefore, evaluation
for GH deficiency is recommended in patients with at least one
KEY POINTS
known pituitary hormone deficiency. Unfortunately, GH ther
• Patients with secondary cortisol deficiency have iso apy has been used inappropriately as an alternative medica
lated glucocorticoid deficiency without mineralocorti tion. GH naturally declines with age and does not require
coid deficiency; in addition, they do not develop hyper replacement. The use of GH does not promote longevity and
pigmentation or bronzing of the skin because when used inappropriately can be harmful. Specifically, GH
adrenocorticotropic hormone and pro-opiomelanocortin therapy can encourage cancer growth, worsening the disease
are not hypersecreted. in a patient with cancer, or promoting growth of an occult,
• Secondary or central hypothyroidism is diagnosed by undiagnosed cancer.
demonstrating a simultaneously inappropriately normal Because GH secretion is pulsatile, testing random levels is
or low thyroid-stimulating hormone and low thyroxine not diagnostically useful. Therefore, GH deficiency is diag
(T) (free or total) level. nosed by measurement of IGF-1. A GH deficiency is confirmed
by measuring the response of serum GH on a stimulatory test,
such as the insulin tolerance test. An insulin tolerance test car
Gonadotropin Deficiency
ries a high risk of severe hypoglycemia, so referral to an endo
The pituitary gland normally secretes LH and FSH in response
crinologist for testing is appropriate.
to GnRH from the hypothalamus. LH and FSH stimulate the
A decision regarding replacement therapy should be
secretion of normal male and female sex hormones; LH and
made based on that patient's symptoms, goals, and risks in
FSH deficiency causes hypogonadotropic hypogonadism (see
consultation with the patient's endocrinologist. When clini
Reproductive Disorders).
cally indicated, GH deficiency is treated with daily subcutane
Hypogonadotropic hypogonadism may be caused by
ous GH injections. In an otherwise healthy adult, treatment of
GnRH deficiency. The most common cause of GnRH defi
GH deficiency can improve quality of life and increase the
ciency in women is hypothalamic amenorrhea, which is
percentage of lean muscle mass. Also, it can reduce the risk of
associated with excess exercise, illness, or anorexia.
osteoporosis. However, the risks and benefits of therapy must
Additional causes of GnRH deficiency include congenital
be carefully considered. Replacement of GH is cost prohibitive
GnRH deficiency and Kallmann syndrome, a condition in
for some patients. It is contraindicated in patients with cancer
which hypothalamic neurons responsible for releasing GnRH
and should not be used in patients with an untreated pituitary
fail to migrate into the hypothalamus during embryonic
tumor due to potential stimulation of tumor growth.
development.
Treatment of hypogonadotropic hypogonadism depends KEY POINT
on the goals of therapy and whether the patient desires fertil • Isolated adult-onset growth hormone deficiency is HVC
ity. Fertility treatment requires replacement of the gonadotro extremely rare, and its clinical significance is debated;
pins in men and women. Premenopausal women who do not evaluation for growth hormone deficiency should be
desire fertility may be treated with estrogen- and progester reserved for adults with at least one known pituitary
one-containing oral contraceptives (after assessment of risk of hormone deficiency.
thromboembolic disease). Treatment of premenopausal hypo
gonadotropic hypogonadism is recommended to avoid loss of Central Diabetes lnsipidus
estrogen-dependent bone at a young age, which could lead to Central diabetes insipidus (DI) results from inadequate pro C]
osteoporosis. Treatment of postmenopausal hypogonadotropic duction of antidiuretic hormone (ADI-!) by the posterior pitui-
hypogonadism is not indicated. Men who do not desire fertility tary gland. In the presence of ADI-!. aquaporin water channels
may be treated with testosterone replacement therapy (see are inserted in the collecting tubules and allow water to be
Reproductive Disorders). reabsorbed. In the absence of ADI-!, excessive water is excreted
by the kidneys. Excretion of more than 3 liters of urine per day
Growth Hormone Deficiency is considered polyul"ic.
Growth hormone (GH) is vital for normal linear growth, and The severity of DI varies with the completeness of the
deficiency prior to puberty will lead to short stature. At puberty, deficiency. Patients describe mild to extreme polyuria and cor
the epiphyses close, halting linear growth. In adulthood, GH responding thirst: partial DI is common.
production is necessary for normal physiology but is not as Frank hypernatremia is unusual because patients develop
important for growth as during childhood. In adults, GH defi extreme thirst and polydipsia, and with free access to water.
ciency causes fatigue, loss of muscle mass, an increased ratio of can maintain serum sodium in the high normal range. When
fatty tissue to lean tissue, and increased risk for osteoporosis. patients do not drink enough to replace the water lost in the
GH deficiency is often the first hormone deficiency to urine, due to poor or absent thirst drive or lack of free access
occur when a patient is developing pituitary insufficiency, but to water. they develop hypernatremia.
24
Disorders of the Pituitary Gland
Cl taneous
CONT.
In the patient with polyuria. DI is diagnosed with simul
laboratory evidence of' inability lo concentrate urine
Pituitary Hormone Excess
Pituitary tumors are called functional when they secrete
in the face or elevated serum sodium and osmolality. with
excessive amounts of hormone. The most common functional
inappropriately low urine osmolality. If' necessary. a water
pituitary tumor is a prolactinoma. GH and ACTH overproduc
deprivation test can confirm the diagnosis (see Table 15).
tion by pituitary tumors is important to recognize because the
Patients with mild partial DI with an adequate thirst drive
clinical consequences of oversecretion are potentially severe.
and access to water may choose to compensate wilhout hor
TSH-secreting tumors cause hyperthyroidism but are
mone replacement therapy, but highly symptomatic polyuria
extremely rare.
and nocturia that interferes with restful sleep and daily func
Occasionally, a pituitary tumor can oversecrete more than
tion necessitate treatment. In those requiring treatment, hor
one hormone, most commonly GH and prolactin, or less com
mone replacement is with desmopressin (J-clesamino 8-D
monly, TSH and GH or prolactin.
arginine vasopressin, or c!DAVP) either intranasally,
subcutaneously, or orally. Desmopressin is not absorbed well in
Hyperprolactinemia and Prolactinoma
the gastrointestinal tract, so oral doses are much higher than
intranasal or subcutaneous doses. Most patients with DI require Causes
either evening dosing to aid in sleep or twice daily closing or Prolactinomas are pituitary tumors that secrete excessive
desmopressin. If ADH is overreplacecl, patients will develop amounts of prolactin; however, they are not the only cause of
water intoxication. volume overload, and hyponatremia. Cl hyperprolactinemia (Table 16).
The most common cause of hyperprolactinemia is phys
KEY POINTS iologic; prolactin is released during pregnancy and postpar
• In the patient with polyuria, diabetes insipidus is diag tum to cause lactation. Nipple stimulation such as during sex
nosed by clinical symptoms with simultaneous labora can cause mild hyperprolactinemia (serum prolactin <40 ng/
tory evidence of inability to concentrate urine mL [40 µg/L]). Physiologic stress, coitus, and exercise can
with elevated semm sodium and osmolality, and inap also increase prolactin levels up to 40 ng/mL (40 µg/L).
propriately low urine osmolality; a water deprivation Nipple piercing can raise prolactin levels above 200 ng/mL
test can confirm the diagnosis. (200 µg/L). Clinical breast examination should not raise pro
• Treatment of central diabetes insipidus is once or twice lactin levels above the reference range, unless evaluation for
daily hormone replacement with desmopressin. milk production is performed, but if desired, palpation of the
breast can be deferred until after a serum prolactin level is
Cl Panhypopituitarism
Panhypopituitarism occurs when patients lack all anterior and
measured.
Medications are a common cause of hyperprolactinemia
(see Table 16). Antipsychotic agents cause hyperprolactinemia
posterior pituitary hormone production. Panhypopituitarism
due to their antidopaminergic effect that interrupts the inhibi
may be caused by a large or aggressive pituitary tumor or as a
tion of prolactin by dopamine. Specific agents, such as risperi
complication of surgery. lf'the pituitary stalk is transected dur
done or metoclopramide, may raise the prolactin level above
ing surgery or as the result of trauma. panhypopituitarism will
200 ng/mL (200 µg/L). Evaluation for pituitary hypersecretion
result acutely. Patients with panhypopituitarism require lite
when a patient is taking a medication known to raise the pro
long replacement ofT 1 , cortisol, and ADH because these defi
lactin level is difficult. When the prolactin level is only mildly
ciencies can be life-threatening. GH and sex hormones are
elevated (<50 ng/mL [50 µg/L]), it may be reasonable to assume
replaced dependent on each patient's preference. coupled
that hyperprolactinemia is a medication side effect. When
with a discussion of the risks and benefits of therapy. In addi
significantly elevated (>100 ng/mL [100 µg/L]), either the
tion to requiring exogenous gonaclotropins to conceive. a
reproductive-aged woman with panhypopituitarisrn will not
go into spontaneous labor and will not lactate. These pregnan TABLE 16. Causes of Hyperprolactinemia
cies are classified as high risk. and obstetric care should be Physiologic Medications Other
provided by a maternal-fetal specialist.
Patients with panhypopituitarism should wear medical Pregnancy Antipsychotic agents• Prolactinoma
25
Disorders of the Pituitary Gland
medication needs to be withheld to further assess or a pitui ceptive pills (if fertility is not desired) or dopamine agonists.
tary MRI obtained to evaluate for prolactinoma. Caution is Postmenopausal women with microadenomas do not require
warranted when discontinuation of an antipsychotic agent is treatment. Patients with hypogonadism from medication
being considered, and consultation with a psychiatrist is rec induced hyperprolactinemia may be treated with hormone
ommended prior to discontinuation. replacement.
Another common cause of hyperprolactinemia is primary Unlike other pituitary tumors, medication rather than
hypothyroidism. Hypothyroidism can cause diffuse swelling of surgery is first-line therapy for prolactinomas. Even patients
the pituitary gland that may resemble enlargement due to a with severe mass effect such as vision loss are treated with
pituitary adenoma on imaging. Therefore, a patient with pri medical therapy initially. Rarely, very large tumors or more
mary hypothyroidism and hyperprolactinemia should be invasive prolactinomas do not shrink with medical therapy
treated with thyroid hormone replacement with retesting of and, also rarely, continue to grow. In these patients, surgery
the prolactin level once the TSH has normalized. Further evalu should be considered, followed by radiotherapy if growth
ation is indicated if the hyperprolactinemia does not correct recurs or continues. After being debulked, the prolactinoma
when hypothyroidism is treated. If pituitary imaging has noted may respond better to medical therapy.
pituitary enlargement prior to treatment of hypothyroidism, Prolactinomas are treated with dopamine agonists (DA).
repeat MRI should be obtained when the TSH is normal. The two FDA-approved dopamine agonists are bromocriptine
Nonfunctioning pituitary adenomas can also cause and cabergoline. Dopamine agonists typically decrease the size
hyperprolactinemia by compressing the pituitary stalk and and hormone production of prolactinomas rapidly. Response
decreasing dopamine inhibition of prolactin secretion. It is to therapy can be monitored by checking serum prolactin
important to distinguish between prolactinomas and non levels 1 month after initiating therapy and then every 3 to
functioning pituitary adenomas as the cause of hyperpro 4 months. Decreasing serum prolactin usually correlates with
lactinemia because of different treatment approaches. decreasing size of the tumor. MRI should be repeated in 1 year
for microprolactinomas if the prolactin level normalizes on
Clinical Features and Diagnosis dopamine agonists. After tumor shrinkage is confirmed, addi
Physiologically, prolactin induces and regulates lactation. tional MR!s are not necessary unless the serum prolactin level
Hence, elevated levels of prolactin cause galactorrhea. Women rises. An MRI should be repeated after 3 months of medical
are more likely to develop galactorrhea than men. therapy for macroprolactinomas, or if prolactin levels are ris
Hyperprolactinemia also causes hypogonadotropic hypo ing on therapy with good medication adherence. MRI should
gonadism because of negative feedback on GnRH, LH, and FSH be repeated every 6 to 12 months until the macroprolactinoma
by high levels of prolactin. Both men and women present with is stable on serial studies and the prolactin level is not rising.
hypogonadism. Women of reproductive age often present ear Bromocriptine is dosed 1 to 3 times daily, so adherence
lier than men because of amenorrhea. They may also have early can be challenging. When initiated, it is associated with
menopausal symptoms. Symptoms in men are insidious and orthostasis and lightheadedness, and patients can have dizzi
may go unrecognized for years. Both men and women with ness, nausea, and headache during treatment. Cabergoline is
hyperprolactinemia are likely to be infertile and are at risk for much better tolerated and more effective at normalizing prol
osteoporosis. Postmenopausal women are already hypogonadal actin and tumor shrinkage, so it is typically the initial therapy
because of ovarian failure; therefore, hyperprolactinemia may chosen. It is dosed once or twice a week, but typically costs
have minimal clinical implications in this population. However, more than bromocriptine.
the cause of postmenopausal hyperprolactinemia still requires Therapy may be tapered after the prolactin level has been
diagnosis because it may be due to a pituitary tumor. normal for 2 years, and there is no longer a visible tumor on
Diagnostic imaging is indicated in situations in which pituitary MRI. After discontinuing the dopamine agonist, pro
there is unexplained hyperprolactinemia. lactin levels should be followed once a month for 3 months,
The degree of hyperprolactinemia is useful in differenti then every 3 months for the first year, and then annually
ating prolactinomas from nonfunctioning macroadenomas. In thereafter; a pituitary MRI should be repeated if the prolactin
general, large nonfunctioning tumors cause mild serum pro level rises above normal.
lactin elevations (<100 ng/mL [100 µg/L]} from stalk compres
sion. Macroprolactinomas raise serum prolactin levels to Prolactinomas and Pregnancy
greater than 250 ng/mL (250 µg/L). Very large macroprolacti Hyperprolactinemia is a frequent cause of infertility because
nomas may raise prolactin levels greater than 10,000 ng/mL of the effect on gonadotropin release. DA therapy lowers pro
(10,000 µg/L). lactin, normalizing gonadotropin regulation and allowing
normal ovulation. DA therapy should be discontinued when
Therapy the pregnancy is diagnosed. The pituitary increases in size
Patients with microprolactinomas without symptoms of during normal pregnancy, and prolactinomas can increase in
hypogonadism do not require treatment. Symptomatic women size as well. The risk for significant tumor expansion is negli
with microadenomas may be treated with either oral contra- gible in patients with microprolactinomas.
26
Disorders of the Pituitary Gland
Women with macroprolactinomas are at risk for clinically Clinical Features and Diagnosis in the Adult
significant tumor growth or vision compromise during preg Patient with Acromegaly
nancy. If the tumor is very large or abuts the optic chiasm, Patients have changes in facial structure such as a prominent
patients should be counseled on risk of tumor growth during brow and jawline, an enlarged skull, a large nose, facial edema,
pregnancy, as well as the risks and benefits of surgical resec excessive spacing between teeth, and macroglossia. The hands
tion of the tumor before pregnancy. DA therapy is sometimes and feet may be disproportionately large. Other manifestations
continued during pregnancy if the patient has a history of may include arthritis, skin tags, diabetes mellitus, hyperten
visual field defect. sion, colon polyps, thickened skin, and excessive perspiration.
Pregnant women with macroprolactinomas should be Acromegaly can cause severe obstructive sleep apnea because
assessed clinically at least once per trimester and have visual of soft-tissue swelling and macroglossia. Additionally, it can
fields tested every trimester or more frequently for vision result in heart disease, including left ventricular hypertrophy,
change. Changes in visual fields or severe headache are indica cardiomyopathy, valvular heart disease, arrhythmia and dias
tions to proceed with pituitary MRI. If the macroprolactinoma tolic hea1i failure. Increased rates of cancer are observed in
causes mass effect during pregnancy, bromocriptine may be acromegaly, including colon, esophageal, and gastric adeno
started. If the bromocriptine does not decrease tumor size and carcinomas; thyroid cancer; and melanoma. Acromegaly
reduce symptoms of mass effect, surgical debulking may be increases mortality, likely due to cardiovascular disease, diabe
necessary. tes, sleep apnea, and cancer. Age-appropriate testing for these
Normal pregnancy causes hyperprolactinemia, so hyper conditions should occur for the lifetime of the patient with
prolactinemia from prolactinoma does not require treatment acromegaly.
during pregnancy. Prolactin levels should not be measured Acromegaly is diagnosed biochemically. Because GH is
during pregnancy. Postpartum, prolactin levels return to pulsatile throughout the day, it is not useful for diagnosis, so
normal within a few months, and lactation becomes non measurement of serum IGF-1 is used instead. Excess GH is
prolactin mediated. confirmed with an oral glucose tolerance test (see Table 15)
because glucose normally suppresses GH levels to less than
KEY POINTS
1 ng/mL (1 µg/L). GH levels greater than 1 ng/mL (1 µg/L) are
• Prolactinomas, pregnancy and lactation, or medications diagnostic of GH excess. A pituitary MRI should be obtained
such as antipsychotic agents are frequent causes of once GH excess is confirmed biochemically. Consultation with
hy perprolactinemia. an endocrinologist is recommended if IGF-1 is elevated.
• A patient with primary hypothyroidism and hyper
prolactinemia should be treated with thyroid hor Treatment
mone replacement with retesting of the prolactin Treatment of acromegaly is transsphenoidal tumor resection;
level once the thyroid-stimulating hormone level has surgery is the only treatment that is potentially curative. In
normalized. many instances, cure with surgery is not possible and addi
tional therapy is necessary to treat the residual GH excess and
• Dopamine agonists (bromocriptine and cabergoline) are
tumor.
first-line therapy for symptomatic patients with hyper
Remission is achieved when IGF-1 levels are within the
prolactinemia and prolactinomas.
normal reference range for age and the response of GH to a
glucose tolerance test is normal. Patients not achieving
Acromegaly remission require medication to decrease GH levels and the
Acromegaly is a rare diagnosis that is often missed for years long-term effects of GH excess. The initial therapy of choice
because of the insidious onset and rare presentation in pri is injectable somatostatin analogues to inhibit GH secretion.
mary care; however, it has very serious implications for a If a patient fails to benefit from somatostatin analogue treat
patient's health and longevity and must be diagnosed and ment, high-dose dopamine agonist therapy is marginally
treated in as timely a manner as possible. effective when the tumor co-secretes prolactin. If IGF-1
remains elevated, pegvisomant, a GH receptor blocker, is
Causes used. Pegvisomant effectively lowers IGF-1 levels, but
Acromegaly is the clinical syndrome that occurs when a pitui patients on pegvisomant have risk of tumor growth because
tary tumor secretes excessive amounts of GH in an adult the medication works in the peripheral tissues as an antag
patient. Prior to puberty, patients with a GH-secreting tumor onist to GH and does not decrease GH production by
develop excessive longitudinal growth and gigantism, a term the tumor.
used to indicate excessive growth and height above normal for Stereotactic radiosurgery (gamma knife) may be offered
age. Because epiphyseal growth plates require sex hormones to to increase the chance of remission or cure. External beam
close, patients with large pituitary tumors causing hypog radiation carries a high risk of causing pituitary insuffi
onadism will not have closure of their growth plates and will ciency, but the risk is decreased when stereotactic radiosur
continue growth into adulthood. gery is used.
27
Disorders of the Pituitary Gland
When acromegaly is in remission, MRI and hormone test Cushing syndrome refers to hypercortisolism rrom any cause.
ing should be completed annually. When the pituitary tumor exogenous or endogenous. ACTH-dependent or not . The mosl
is stable but the IGF-1 level is elevated, MRI should be repeated common cause or endogenous Cushing syndrome is Cushing
annually and treatment should be altered until the IGF-1 disease. When undiagnosed. Cushing disease is associated
declines. with devastating Jong term morbidity such as diabetes. mor
bid obesity. hypertension. infertility. and osteoporosis.
KEY POINTS
The initial step in evaluation for Cushing disease is to seek
• Acromegaly occurs when a pituitary tumor secretes biochemical evidence or hypercorlisolism (see Disorders or Lhe
excessive amounts of growth hormone in an adult Adrenal Glands).
patient resulting in changes in facial structure, an Once ACTH-dependent Cushing syndrome is confirmed
enlarged skull, a large nose, facial edema, excessive biochemically. a pituitary MRI should be obtained. Ir no pitui
spacing between teeth, macroglossia, and dispropor tary tumor or a tumor less than 6 mm is visualized on MRI. an
tionately large hands and feet. 8 mg dexamethasone suppression test is used to dil'Jerentiale
• Treatment of acromegaly is transsphenoidal tumor Cushing disease from an ectopic source of ACTH. Ectopic
resection; however, in some patients, adjuvant radiation ACTH production f'rom a nonpiluitary tumor (most often lung.
therapy or medical therapy, such as injectable somato pancreas. or thymus carcinomas) is very uncommon.
statin analogues, is needed for residual disease. Dexamethasone is administered al JI Pill. and cortisol is
lesled al 8 AM. A pituitary source of' ACTH will respond lo
negative feedback rrom high doses or dexamethasone. sup
Gonadotropin-Producing Adenomas
pressing cortisol to Jess lhan 5 µg/dL (l38 nmol/L). while an
Gonadotropin-producing pituitary adenomas are typically
ectopic source of' ACTH will not have suppressible cortisol.
asymptomatic and are treated similarly to nonfunctioning
J Jowever. this test has low sensitivity (88%) and specificity
adenomas because they either do not secrete functional gon
(STX,) for Cushing disease. so intrapelrosal sinus sampling
adotropins or do not secrete enough FSH or LH to produce a
(I PSS) is often recommended before exploratory pituitary sur
clinical syndrome. Often, the diagnosis is made postopera
gery. In IPSS. a catheter is threaded through the petrosal sinus.
tively, based on histopathologic staining of surgical pathology
and ACTH levels in the sinus are compared with those in the
specimens.
periphery af'ler the administration or corticotropin-releasing
hormone (CRH). A central lo peripheral gradient greater than
Thyroid-Stimulating Hormone-Secreting Tumors
2.0 betore CRH or greater than 3.0 after CRH is diagnostic of
TSH-secreting tumors are extremely rare. These tumors may
Cushing disease (95% sensitivity. 93% specificity). Imaging of'
co--secrete TSH and prolactin or GH. TSH-secreting tumors
the chest and abdomen is indicated in patients with a sus
cause hyperthyroidism. Patients with TSH-secreting tumors
pected ectopic source of ACfH.
have either an inappropriately normal or a high TSH level
with a simultaneous elevation ofT4 and T 3 levels. They pre Treatment
sent with identical symptoms associated with non-TSH Cushing disease is treated by Lranssphenoidal pituitary
mediated thyrotoxicosis (see Disorders of the Thyroid Gland). tumor resection. which may be curative. Endogenous ACTH
After biochemical proof of TSH excess is obtained, pituitary production in the remaining normal pituitary gland will be
imaging is recommended to confirm a pituitary mass. suppressed af'ler removal or the tumor due to long-standing
Neurosurgery is first-line therapy, but patients often require hypercortisolism. so patients with successful surgical treat
additional medical therapy with either somatostatin ana ment will have acute ACTH deficiency and require gluco
logues or dopamine agonists. corticoid replacement. It may take up to J year for
endogenous ACTH production to return to normal. and
Excess Antidiuretic Hormone Secretion sometimes the hypothalamic-pituitary adrenal axis does
The syndrome of inappropriate ADH secretion (SlADH) causes not recover. After successful resection. Cushing disease can
water retention and hyponatremia. Central nervous system recur. and patients musl be monitored annually ror several
pathology such as stroke, hemorrhage, trauma, or infection yeus . .:incl then less frequently. or sooner if' symptoms of'
can cause SIADH because of the excessive release of hypotha hypercorlisolism recur.
lamic and pituitary ADH. Also, transient SIADH is a common Ir surgical cure is not achieved. patients may be offered
complication of pituitary surgery, occurring in about one third pituitary radiation or medical therapy. Medic.:il options include
of patients approximately 3 to 10 days after surgery (see inhibitors or adrenal enzyme synthesis of cortisol, ketocona
MKSAP17 Nephrology). zole. or metyrapone: the dopamine agonisl, cabergoline; or the
somalostatin analogue. pasireotide. Medical cure or Cushing
Cl Cushing Disease
Cushing disease is Lhe term used to indicate excess cortisol
disease has a relatively low success rate. but hypercortisolism
symptom control is an achievable goal in all patients with
production clue to an ACTH-secreting pituitary adenoma . endogenous Cushing syndrome.
28
Disorders of the Adrenal Glands
l"l"I In patients who do not benef'it f'rom surgicil treatment Synthesis of adrenal androgens, dehydroepiandrosterone
LI.I and who have an inadequate response Lo medical treat (DHEA) and its sulfate (DHEAS), and androstenedione, occurs
CONT.
ment, bilateral aclrenalectomy to remove the target of" ACTH primarily in the zona reticularis and is regulated by ACTH.
stimulation is an option. However. these patients will Although the adrenal androgens themselves have minimal
require lifelong glucocorticoicl and mineralocorticoicl intrinsic androgenic activity, they are converted peripherally
replacement. Cl to testosterone and dihydrotestosterone. Unlike glucocorti
coids and mineralocorticoids, deficiencies of adrenal andro
KEY POINTS
gens are not typically recognized clue to parallel production of
• Cushing disease refers to excess cortisol production clue gonadal androgens.
to an adrenocorticotropic hormone (ACTH)-secreting The adrenal medulla and extra-adrenal sites of the sym
pituitary adenoma; Cushing syndrome refers to hyper pathetic nervous system consist of chromaffin cells, which
cortisolism from any cause, exogenous or endogenous, synthesize catecholamine hormones from the amino acid
ACTH-dependent or not. tyrosine (Figure 4). Catecholamines are stored within chro
• Cushing disease is treated by transsphenoidal pituitary maffin granules, which release their contents in response to
tumor resection; after surgery glucocorticoid replace stress. Although catecholamine excess produces disease,
ment therapy will be required at least transiently while hypofunction of the adrenal medulla does not because of
the hypothalamic-pituitary-adrenal axis recovers redundancy of catecholamine production throughout the
endogenous function. sympathetic nervous system. Norepinephrine is synthesized in
the adrenal medulla and the extra-adrenal sites of the sympa
thetic nervous system. It causes vasoconstriction due to pref
Disorders of the erential binding to a-receptors. Epinephrine is almost
exclusively produced in the adrenal medulla. It binds pre
Adrenal Glands dominantly to �-receptors, and thus has positive effects on
cardiac inotropy and chronotropy, produces peripheral vaso
Adrenal Anatomy and Physiology dilation, and increases plasma glucose levels in response to
Located just superior to each kidney, the paired adrenal glands hypoglycemia.
consist of an outer cortex and an inner medulla that are dis
tinct in embryologic origin and endocrine function. The adre
nal cortex is composed of three zones: the zona (outer) glo Tyrosine
merulosa, zona (middle) fasciculata, and zona (inner)
reticularis. Within these zones corticosteroid hormones are
synthesized from cholesterol by cytochrome P450 enzymes.
J0
Aldosterone, the principal mineralocorticoid hormone, is pro �
duced in the zona glomerulosa. Aldosterone production is
triggered by an increase in the extracellular potassium con
centration and by activation of aldosterone synthase through Dopamine
�-��'---�
The zona fasciculata is the main site of glucocorticoid Epinephrine Metanephrines
synthesis. Production of cortisol, the principal glucocorti
coid, is stimulated by adrenocorticotropic hormone (ACTH) CD CD
secretion from the anterior pituitary. Cortisol secretion
varies according to the circadian rhythm with relatively ____Cl_ihydroxymandelic acid � �anillylmandelic acid
29
Disord ers of the Adrenal Glands
Adrenal Hormone Excess Clinical manifestations of CS are listed in Table 18. Clinical
findings that are highly specific for CS include centripetal obe
Cushing Syndrome
sity, facial plethora, abnormal fat deposition in the supraclav
Cushing syndrome (CS) is a rare disorder affecting two to three icular or dorsocervical ("buffalo hump") areas, and wide (>l
persons per million per year that results from elevated levels of cm) violaceous striae (Figure 5). It is important to initiate
cortisol. Poor suppressibility of cortisol with dexamethasone evaluation for CS in patients who have specific signs and
and loss of normal diurnal variation in cortisol secretion are symptoms of CS, rather than in patients who are diffusely
seen. Without treatment, it is associated with high morbidity obese, have nonpathologic striae, and are having trouble losing
and mortality. weight because endogenous CS is such a rare condition with a
However, iatrogenic hypercortisolism from the admin costly evaluation algorithm.
istration of exogenous oral, inhaled, intra-articular, or topi Biochemical testing is used to establish the diagnosis of CS.
cal glucocorticoids is often seen in clinical practice and is It is critical that the biochemical diagnosis is firmly established
the most common cause of CS overall. The pharmacokinetics prior to any imaging studies due to the relatively high prevalence
and relative potencies of synthetic oral glucocorticoids are of clinically insignificant pituitary and adrenal nodules. At least
shown in Table 17. The sustained administration of any syn two first-line tests should be diagnostically abnormal before the
thetic glucocorticoid above the normal physiologic cortisol diagnosis is confirmed. Initial tests include the overnight low
requirement can result in iatrogenic CS and hypothalamic dose dexamethasone suppression test (LOST), 24-hour urine
pituitary-adrenal (HPA) axis suppression, but is more likely free cortisol (UFC), and late-night (LN) salivary cortisol. All three
to occur the longer the half-life of the drug. Doses equivalent tests have similar diagnostic utility, but the LOST or LN salivary
to prednisone 5 mg/d or less are unlikely to cause clinically cortisol tests are more convenient. The 24-hour UFC and LN
significant HPA axis suppression, while those in excess oflO salivary cortisol tests should be performed at least twice to
to 20 mg/d commonly do after 3 weeks or more of consecu ensure reproducibility of results. Because the secretion of corti
tive use. sol is pulsatile, measurement of random serum cortisol is neither
Endogenous CS can result from ACTH-dependent and sensitive nor specific for the diagnosis of CS. An algorithm to
ACTH-independent causes. Cushing disease, which results establish the diagnosis of CS is shown in Figure 6. Referral to an
from the autonomous secretion of ACTH by a corticotroph endocrinologist is indicated if two initial tests are abnormal.
adenoma of the pituitary gland, is the cause of CS in more than
two thirds of patients (see Disorders of the Pituitary Gland).
Ectopic ACTH secretion by carcinomas and carcinoid tumors
(usually bronchial origin) is less common, accounting for 10%
to 15% of cases, while ectopic corticotropin-releasing hormone
(CRH) production is rare. The most common ACTH
independent etiologies of CS are adrenal adenomas and carci
nomas, which collectively account for approximately 20% of
CS cases.
CS must be differentiated from other disorders and clini
cal states that are associated with physiologic hypercortisolism
(pseudo-Cushing syndrome). Causes of pseudo-Cushing syn
drome include severe obesity, polycystic ovary syndrome, f I GU RE 5. Wide violaceous striae are seen on the abdomen of a patient with
pregnancy, anorexia nervosa, depression, alcoholism, and Cushing syndrome. Striae larger than 1 cm in width are highly specific for hyper
extreme physical stress, as in the setting of infection. cortisolism.
TABLE 17. Dose Equiyal!'!C:�.<!_nd -�j�t.i_v� !:'oteric�es <>f Co mmon Syn�h�tic_Oral Glucocorticoids
Synthetic Glucocorticoid Equivalent Biologic Relative Anti- Relative
Replace ment Half-Life Infla mmatory Mineralocorticoid
Dose ( mg)• (hours) Potencyh Potency c
30
Disorders of the A drenal Glands
TABLE 18. Clinical Features of Cushing Syndrome other proteins. Therefore the LDST should not be performed
Specific Findings Less Specific Associated
when CBG is likely to be abnormal, such as with malnutrition,
Findings Conditions• cirrhosis, the nephrotic syndrome, and hyperestrogenemia
(oral contraceptive pills or pregnancy). There is no clear asso
Centripetal obesity Easy bruising Osteoporosis
ciation between dexamethasone responses and BM! or weight,
Facial plethora Excessive skin Hypertension and therefore the LDST may be used similarly in the obese
fragility
Supraclavicular fat Diabetes mellitus population. The LDST is best avoided in patients taking medi
pads Proximal muscle
Obesity cations that could accelerate dexamethasone metabolism,
weakness
Dorsocervical fat such as antiepileptic drugs (phenytoin, phenobarbital, and
Depression
pads Impaired memory
carbamazepine), rifampin, or pioglitazone. Concomitant
Hypokalemia
Wide violaceous Temporal balding b
measurement of serum dexamethasone can confirm altered
striae Nephrolithiasis
Hirsutism (in dexamethasone metabolism and patient adherence.
women) b VTE/PE Measuring 24-hour UFC circumvents problems related to
Menstrual cortisol pulsatility and binding protein abnormalities. The test
abnormalitiesb
should be performed at least twice to ensure accuracy. To con
PE= pulmonary embolism; VTE= venous thromboembolism. firm adequate collection, 24-hour urine creatinine is also
aMedical disorders that may be seen in association with but are not specific for measured (normal range, 20-25 mg/kg/24 h [177-221 mmol/
Cushing syndrome.
kg/24 h] in men; 15-20 mg/kg/24 h [133-177 mmol/L/24 h] in
bFeatures of androgen excess seen with pituitary corticotroph adenoma or adreno
cortical carcinoma.
women). A test is considered abnormal when UFC exceeds the
upper limit of the normal range of the assay (45 µg/24 h [124
nmol/24 bl), while values greater than 3 times normal are
diagnostic of CS. Less marked elevations are seen with pseudo
In the standard LOST, dexamethasone (0.5 mg) is admin Cushing syndrome and polyuria. A falsely low UFC can occur
istered every 6 hours for 48 hours and serum cortisol is meas in chronic kidney disease and when CS is subclinical or mild.
ured at 9 AM. In the overnight LDST, 1 mg of dexamethasone is The LN salivary cortisol test is performed between 11 PM
administered at 11 PM or midnight, and serum cortisol is meas and midnight. The normal evening nadir in cortisol secretion
ured the next morning at 8 AM. With either test, serum cortisol is lost in patients with CS, while it is preserved in patients with
will typically be suppressed to less than 2 µg/dL pseudo-Cushing syndrome. Both emotional and physical
(55 nmol/L). Standard assays measure total serum cortisol, or stress (for example, exercise) can cause a physiologic increase
that which is bound to cortisol-binding globulin (CBG) and of salivary cortisol. False-positive results are seen with
Abnormal: Normal
Exclude physiologic
hypercortisolism
Physiologic Physiologic
hypercortisolism hypercortisol ism 1--- - -
.. 1 CS unlikely I
excluded suspected
Normal:
Abnormal: Additional
Repeat initial abnormal
CS confirmed testing
test; do additional tests
FIGURE 6. Algorithm to confirm or rule out the diagnosis of Cushing syndrome. CS= Cushing syndrome; DST= dexamethasone suppression test; LN salivary
cortisol = late-night salivary cortisol; UFC = urine free cortisol.
AMust be performed at least twice.
31
Disorders of the Adrenal Glands
cigarette smoking or use of chewing tobacco. LN salivary cor suppression and contralateral adrenal atrophy from long-stand
tisol testing should not be performed in patients with erratic ing elevated cortisol levels. All patients should therefore be treated
sleep schedules (for example, shift-workers). with stress-dose glucocorticoids during the petioperative petiod
After CS has been confirmed biochemically, further testing and continued on physiologic replacement until HPA axis recov
is required to distinguish ACTH-dependent or -independent ery has been confirmed. Following successful surgery, the physi
causes, and consultation with an endocrinologist is recom cal changes associated with CS can take up to 1 year to resolve.
mended. The first step is to measure plasma ACTH on two
KEY POINTS
separate occasions. With adrenal (ACTH-independent) CS,
plasma ACTH is usually less than S pg/mL (1.1 pmol/L), • Cushing syndrome results from endogenous hypercorti
whereas values greater than 20 pg/mL (4.4 pmol!L) are typi solism or exogenous exposure to glucocorticoids; it is
cally seen with ACTH-dependent causes. Plasma ACTH values associated with poor suppressibility of endogenous cor
of S to 20 pg/mL (1.1-4.4 pmol/L) are nondiagnostic but are tisol production with oral dexamethasone.
more likely to be seen with ACTH-dependent disorders. For a • The most common cause of Cushing syndrome is the
discussion of the evaluation and management of ACTH administration of exogenous glucocorticoid therapy for
dependent CS, see Disorders of the Pituitary Gland. another medical condition.
The next step in the evaluation of ACTH-independent CS is • Initial tests for Cushing syndrome include the overnight
with imaging of the adrenal glands, such as dedicated adrenal low-dose dexamethasone suppression test, 24-hour
imaging with thin-section CT or MRI. Both studies have equal urine free cortisol, and late-night salivary cortisol.
sensitivity; however, MRI is more costly. Adrenal adenomas and
carcinomas can usually be distinguished from one another Pheochromocytomas and Paragangliomas
radiographically (Table 19). Surgery is considered first-line Paragangliomas are tumors composed of chromaffin cells.
treatment for adrenal adenomas and nonmetastatic adrenocor Approximately 80% are intra-adrenal (pheochromocytomas);
tical carcinomas (ACCs). When surgery is delayed for patients the rest originate from extra-adrenal sympathetic or parasym
with overt CS, adrenal enzyme inhibitors (metyrapone, keto pathetic paraganglia. The most common location for extra
conazole, and etomidate) can be used to reduce cortisol levels adrenal sympathetic paragangliomas is the abdomen, whereas
and decrease the risk of complications, such as opportunistic parasympathetic paragangliomas are usually found in the head
infections and cardiovascular events. The management of ACC and neck. Pheochromocytomas and extra-adrenal sympathetic
is discussed elsewhere (see Adrenocortical Carcinoma). paragangliomas almost always secrete catecholamines (norepi
Following adrenalectomy, patients with adrenal CS will nephrine, epinephrine, dopamine); however, head and neck
often develop acute adrenal insufficiency because of HPA axis parasympathetic paragangliomas almost never do.
32
Disorders of the Adrenal Glands
Although catecholamine-secreting tumors are rare over low (adrenal mass without typical radiographic appearance),
all, they are found in 0.5% of patients with hypertension, and while measurement of plasma free metanephrines is preferred
pheochromocytomas account for 5% of adrenal incidentalo when clinical suspicion is higher (known hereditary syn
mas (see Incidentally Noted Adrenal Masses). Most pheochro drome). Referral to an endocrinologist is recommended when
mocytomas secrete norepinephrine, resulting in episodic or biochemical testing is abnormal.
sustained hypertension. Orthostatic hypotension can also be Many medications and other substances cause falsely
seen and likely reflects low plasma volume. In addition to the high levels of plasma and urine catecholamines or metane
classic triad of diaphoresis, headache, and tachycardia, com phrines (Table 21); therefore, discontinuation of these agents
mon symptoms include palpitations, tremor, pallor, and anxi before testing is recommended. If a catecholamine-secreting
ety. Less common features are papilledema, diabetes mellitus, tumor is strongly suspected in a critically ill hospitalized
and cardiomyopathy. Approximately 10% of pheochromocyto patient, CT or MRI of the abdomen is the preferred initial test
mas and 20% to 50% of paragangliomas are malignant. because biochemical testing cannot be interpreted reliably in
One third of pheochromocytomas and paragangliomas this setting.
occur in the context of a genetic disorder. Pheochromocytomas Following the biochemical diagnosis of pheochromocy
are seen with multiple endocrine neoplasia (MEN) syndromes toma or catecholamine-secreting paraganglioma, radiographic
type 2A and 2B (Table 20), neurofibromatosis type 1, and von localization is needed. Because most catecholamine-secreting
Hippel-Lindau syndrome (VHL). Paragangliomas and, less tumors are located in the abdomen, CT or MRI of the abdomen
frequently, pheochromocytomas can occur with familial para and pelvis is the best initial study. If negative, iodine 123
(123 1
ganglioma syndrome mutations, some of which are associated )-metaiodobenzylguanidine (MIBG) scanning can be per
with high rates of malignancy. formed. Adjunctive diagnostic tests are CT or MRI of the chest
The diagnosis of pheochromocytoma and paraganglioma or head and neck region.
is based on confirmation of the excessive secretion of catecho When multiple tumors or malignant pheochromocyto
lamines or their metabolites, as measured in the plasma or mas or paragangliomas are suspected, MIBG scanning should
urine. Evaluation is recommended, if clinically suspected, in be performed preoperatively. However, for identification of
the evaluation of an incidentally noted adrenal mass or in the metastatic disease, fluorine 18 (18 F)-fluorodeoxyglucose (FOG)
setting of hereditary pheochromocytoma or paraganglioma PET scanning is superior to other diagnostic tests.
syndromes. The sensitivity of plasma free metanephrines is Preoperative pharmacologic treatment is mandatory for
the highest of any screening test (96%-100%); however, its pheochromocytomas and paragangliomas to prevent life
specificity is relatively low (85%-89%). Therefore, plasma free threatening cardiovascular complications related to the mas
metanephrines will reliably exclude a pheochromocytoma sive release of catecholamines during surgery. Preoperative
when negative, but further testing is needed to confirm the blockade of a-adrenoceptors, usually with phenoxyben
diagnosis unless the result is markedly abnormal (above 4 zamine, is first-line medical therapy. The dosage is titrated to
times the upper limit of normal). The sensitivity and specific achieve a blood pressure below 130/80 mm Hg seated and
ity of 24-hour urine fractionated metanephrines and catecho greater than 90 mm Hg (systolic) standing. Commonly used
lamines are 91% to 98%. Due to the lower frequency of but non-FDA approved alternatives include calcium channel
false-positive results, 24-hour urine measurements are recom blockers and selective a1 -blockers (terazosin or doxazosin).
mended when the pre-test probability of disease is relatively �-Adrenoceptor blockers (metoprolol or propranolol) are
MEN1 (inheritance of one mutated Parathyroid adenoma Pancreatic islet cell and enteric tumors (gastrinoma, insulinoma
allele with somatic mutation in (often multiple) most common)
other allele leads to neoplasia)
Pituitary adenoma
Other (carcinoid tumors, adrenocortical adenoma)
33
Disorders of the Adrenal Glands
34
Disorders of the Adrenal Glands
TABLE 22. The Effect of Commonly Prescribed : lemia with undetectable PRA and PAC greater than 30 ng/dL
Medications on Measurements of Plasma Renin Activity and (828 pmol/L). Confirmatory tests include oral and intravenous
Plasma Aldosterone Concentration ', salt loading and the fludrocortisone suppression and captopril
Effect on Test Medication Class PRA PAC PAC/ challenge tests (Table 23).
Results PRA Once the diagnosis or PA has been confirmed biochemi
False-Positive a-Adrenoceptor J,J, J, i cally, radiographic localization with abdominal CT is indi
agonist cated. CT is recommended over MRI in most cases due to
P-Adrenoceptor J,J, J, i similar efficacy and lower cost. Adrenal hyperplasia and
blocker aclenomas can often be visualized and aclrenocortical carci
Direct renin J, J, i noma can be ruled out. Adrenal vein sampling (AVS) is
inhibitor needed in most patients to determine the source of aldoster
NSAID J,J, J, i one secretion when imaging is unrevealing and to confirm
False-Negative ACE inhibitor/ARB ii J, J, lateralization when imaging demonstrates an adrenal ade
noma. AVS is especially important in older patients (40 years
Dihydropyridine i J, J,
CCB and older) because of a higher frequency of nonfunctioning
Diuretic• ii i J,
adrenal incidentalomas. AVS should be performed at experi
enced centers only.
Mineralocorticoid ii i J,
receptor The goals of treatment include improvement in blood
antagonist pressure (resolution of hypertension is unlikely). normali
SSRI i J, zation of serum potassium (this is very likely) , and reduc
tion in plasma aldosterone because hyperaldosteronemia is
ARB= angiotensin receptor antagonist; CCB = calcium channel blocker; PAC =
plasma aldosterone concentration; PRA = plasma renin activity; SSRI = selective associated with a blood pressure-independent increase in
serotonin reuptake inhibitor.
cardiovascular events. The treatment of choice for PA clue
asoth potassium-sparing (amiloride) and potassium-wasting (hydrochlorothiazide)
diuretics.
to APA or unilateral adrenal hyperplasia is Japaroscopic
aclrenalectomy.
Cl
For patients with bilateral adrenal hyperplasia or those
can be continued, but results must be interpreted in context. with unilateral causes of PA who are not surgical candidates.
For example, if PRA is suppressed despite treatment with an medical therapy with a mineralocorticoid antagonist is indi
CONT.
ACE inhibitor or angiotensin receptor blocker. PA is likely. If cated. Spironolactone is the most commonly used medication
results are difficult to interpret, repeat testing after eliminating due to its proven efficacy and cost-effectiveness. Eplerenone
potential interfering medications is advised. Verapamil. is less likely to cause side effects (gynecomastia in men and
hydralazine, and ex-blockers (doxazosin) can be substituted for menstrual irregularities in women) because of greater miner
blood pressure control if necessary. Referral to an endocrinolo alocorticoid receptor selectivity. Amiloride is a potassium
gist is recommended when screening tests are abnormal. sparing diuretic that blocks the aldosterone-sensitive sodium
Confirmatory testing is performed except when initial channel. Use of'amiloride in PA is second-line therapy because
testing is diagnostic for PA, as in cases of spontaneous hypoka- of lower efficacy. Cl
Captopril Administer: Captopril2 5-50 mg orally after the patient has been PAC remains elevated and PRA suppressed
challenge test seated for 1 hour
(Normal response is suppression of PAC by
Measure: PAC, PRA, and cortisol at O and 1 or2 hours while seated >30%)
Fludrocortisone Administer: Fludrocortisone0. 5 mg orally every6 hours for4 days PAC>6 ng/dl (165.6 pmol/L)
suppression along with sodium and potassium supplementation
PRA <1 ng/mUh (1 µg/Uh)
test
Measure: Serum cortisol at7 and 10 AM, and PAC and PRA at
(Cortisol at 10 AM lower than 7 AM)
10 AM on day4
Oral salt Administer: Sodium chloride 6 g orally daily (in divided doses)for 24-hour urine aldosterone>12 µg
loading test 3 days
(Urine Na>200 mEq [220 mmol/L])
Measure: 24-hour urine aldosterone and urine Na on the third day
Intravenous salt Administer: 2 L0. 9% saline intravenously over4 hours while supine PAC>10 ng/dl (276.0 pmol/L)
loading test
Measure: PAC, PRA, cortisol, and serum Kat O and4 hours
IM = intramuscular; IV= intravenous; K = potassium; Na = sodium; PAC= plasma aldosterone concentration; PRA = plasma renin activity.
35
Disorders of the Adrenal Glands
KEY POINTS have at least one other autoimmune endocrine disorder, and
more than 80% have adrenal autoantibodies (21-hydroxylase
• Testing for primary hyperaldosteronism is with the
antibodies). Infiltration of the adrenal glands by tuberculosis
simultaneous measurement of midmorning ambulatory
(Addison disease) was formerly the most common etiology of
plasma renin activity and plasma aldosterone levels;
primary adrenal failure; now it is responsible for only 7% to
testing is positive if plasma aldosterone concentration is
20%. Replacement of the adrenal glands can also occur with
frankly elevated (>15 ng/dL [414 pmol/L]), plasma renin
metastatic cancer. Genetic causes include autoimmune poly
activity is suppressed, and a ratio of the former over the
glandular syndromes (APS) type 1 and 2, congenital adrenal
latter is greater than 20.
hyperplasia, and X-linked adrenoleukodystrophy. Adrenal cri
• The treatment of choice for primary hyperaldosteronism sis resulting from bilateral adrenal hemorrhage can occur with
due to an aldosteronoma or unilateral adrenal hyperpla the antiphospholipid syndrome, disseminated intravascular
sia is laparoscopic adrenalectomy; for patients with coagulation, or systemic anticoagulation.
bilateral adrenal hyperplasia or those with unilateral The clinical presentation of primary adrenal failure
causes of primary hyperaldosteronism who are not can depends on disease chronicity and the presence of physical
didates for surgery, medical therapy with a mineralocor stressors. In autoimmune adrenalitis, the zona glomerulosa is
ticoid antagonist such as spironolactone is indicated. usually affected first, which is manifest by an increase in PRA.
With involvement of the zona fasciculata, a diminished corti
Androgen-Producing Adrenal Tumors sol response to ACTH is seen, followed by an increase in basal
Pure androgen-secreting adrenal neoplasms are very rare. plasma ACTH, and lastly a decrease in serum cortisol. Patients
These tumors usually secrete DHEA and DHEAS and/or typically do not have symptoms until hypocortisolemia occurs.
androstenedione, which are converted peripherally to testos Table 24 shows the clinical and laboratory manifestations of
terone. Approximately half of androgen-producing tumors are primary adrenal failure. Hyperpigmentation is a clinical hall
benign and half are malignant. Manifestations of androgen mark of this disorder that is not seen with secondary cortisol
producing adrenal tumors are usually absent in adult men, deficiency (seeDisorders of the Pituitary Gland for discussion
although decreased testicular volume can occur. In women, of secondary cortisol deficiency).
rapid onset of hirsutism, menstrual irregularities, and viriliza Adrenal crisis may occur when onset of adrenal failure is
tion can be seen and, if present, should raise suspicion for abrupt (bilateral adrenal hemorrhage) or when increased
tumoral hyperandrogenism. Signs of virilization are deepen stress occurs in the setting of chronic adrenal failure.
ing of the voice, clitoromegaly, and temporal hair loss. The Manifestations of adrenal crisis include shock, hypotension,
diagnosis of an androgen-producing adrenal tumor is based fever, nausea, vomiting, abdominal pain, tachycardia, and
on demonstrating elevated levels ofDHEA and its sulfate (usu even death. Aldosterone is critical to the maintenance of intra
ally greater than 800 µg/dL [21.6 µmol/L]) and/or androsten vascular volume and blood pressure, while cortisol contrib
edione. Although adrenal androgen excess can be seen in 30% utes to augmentation of blood pressure mostly during times of
to 40% of women with polycystic ovary syndrome, mild eleva increased physical stress (see Adrenal Anatomy and
tion ofDHEAS (approximately 300 µg/dL [8.1 µmol/L) is typi Physiology). Aldosterone deficiency is the major impetus for
cal. Adrenal imaging with CT or MRI is indicated following the development of hypotension and shock in patients with
biochemical diagnosis of disease to locate the tumor. Treatment untreated primary adrenal failure. Adrenal crisis is rare in the
is surgical removal of the tumor. setting of secondary cortisol deficiency because the renin
angiotensin-aldosterone pathway is intact.
36
D i s orders of the Adrenal Glands
Nausea/vomiting
Abdominal pain
Arthralgia
Myalgia
Aldosterone Salt craving Orthostasis iPRA
Dizziness Hypotension -1. Serum sodium
i Serum potassium
DHEAS Reduced libido• Decreased axillary or pubic hair• -1. Serum DHEAS
ACTH= adrenocorticotropic hormone; BP= blood pressure; DHEAS = dehydroepiandrosterone sulfate; PRA = plasma renin activity.
"Women only.
ccortisol inhibits the secretion of antidiuretic hormone (ADH), so hypocortisolemia will lead to increased secretion of ADH and hyponatremia.
dRare in adults.
for diagnosis in the critical care setting (see Adrenal Function longer-acting glucocorticoids (prednisone or dexamethasone)
During Critical Illness). is acceptable. All patients with cortisol deficiency need to
Once the diagnosis of cortisol deficiency has been estab receive instructions for increasing their cortisol replacement
lished, measurement of 8 AM plasma ACTH will differentiate dose during illness ("sick day rules''). Patients should always
primary and secondary causes. In primary adrenal failure, wear a medical alert identification.
ACTH is typically greater than 200 pg/mL (44 pmol/L), In contrast to patients with secondary cortisol deficiency
whereas it will be low or inappropriately normal in secondary (see Disorders of the Pituitary Gland), those with primary
cortisol deficiency. Although not specific for the diagnosis, adrenal failure also require mineralocorticoid replacement.
hyponatremia and hyperkalemia are characteristic of primary Usual doses are 0.05 to 0.2 mg per day of fludrocortisone.
adrenal failure and principally result from aldosterone defi Measurements of serum sodium and potassium help guide
ciency. dosing. Replacement of DH EA is controversial. It is not indi
cated for men but can be considered for some women with
Treatment primary adrenal failure. However, the objective benefit is min
Without appropriate treatment, primary adrenal failure is imal, and there are concerns regarding the quality and safety
uniformly fatal. Even when treated. the mortality of patients is of U.S. preparations where DH EA is considered a supplement
twice that of the general population. Normal adrenal physiol rather than a pharmaceutical.
ogy cannot be reproduced exactly by the administration of Patients who present emergently with suspected adrenal
exogenous glucocorticoids and mineralocorticoids. Moreover. crisis should be treated empirically prior to confirmation of
the administration of doses of glucocorticoid in excess of the diagnosis. A blood sample should be drawn for serum
physiologic replacement can be associated with decreased cortisol, plasma ACTH. and routine chemistries. The patient
bone mineral density and features ores. with increased risk of should receive immediate treatment with 100 mg of hydro
metabolic syndrome. type 2 diabetes mellitus. hypertension , cortisone intravenously and aggressive fluid resuscitation.
hyperlipidemia. obesity, and cardiovascular disease. Avoidance Hydrocortisone is continued at 100 to 200 mg per day in
of chronic overreplacement is paramount. divided closes (every 6-8 hours) and then tapered to physio
Table 25 shows the medical treatment for primary adrenal logic replacement if cortisol deficiency is confirmed with the
failure. Most patients require glucocorticoid doses equivalent above testing. Other synthetic glucocorticoids can also be
to 12.5 to 25 mg of hydrocortisone daily. Hydrocortisone is used for the treatment of adrenal crisis; however. only hydro
administered 2 to 3 tin1es daily. while once daily dosing of cortisone in supraphysiologic doses has clinically relevant
37
Disord e rs of the Adrenal Glands
'
,TABLE 25. Chronic Medical Treatment of Primary Adrenal Failure , .
Medication Basal Dose Considerations
Glucocorticoid a
Hydrocortisone "Sick Day Rules": patient follows at home
Hydrocortisone Usually 12.5-25 mg/d, divided into For minor physiologic stress (upper respiratory infection, fever, minor
2-3 doses over the day surgery under local anesthesia)
Prednisone
Alternatives to hydrocortisone: 2-3 times basal dose for 2-3 days
Prednisolone
Prednisone 2.5-5 mg once daily Stress Dosing: health care providers follow while patient is in the hospital
Dexamethasone
Dexamethasone 0,25-0.75 mg once For moderate physiologic stress (minor or moderate surgery with general
daily anesthesia)
How to dose: Hydrocortisone 45-75 mg/d orally or IV in 3-4 divided doses for 2-3 days
Titrate to clinical response with goal Alternatives: Prednisone 10-20 mg or dexamethasone 2-3 mg/d in
of no signs or symptoms of cortisol 1-2 divided doses
deficiency or excess (increase dose if
For major physiologic stress (major surgery, trauma, critical illness, or
symptoms of cortisol deficiency
childbirth)
remain; decrease if CS signs and
symptoms are present) Hydrocortisone 150-200 mg/day IV in 3-4 divided doses; 100 mg/day the
next day; taper to baseline in 3-5 days
Alternative: Dexamethasone 6-8 mg/d IV in 2-3 divided doses
Mineralocorticoid 0.05-0.2 mg once daily in the morning Fludrocortisone is not required if hydrocortisone dose >50 mg/d
Fludrocortisone How to dose:
Titrate to
1. Normal BP
2. Normal serum Na, K
Adrenal 25-50 mg once daily Consider DHEA for women with impaired mood or sense of well-being
androgen when glucocorticoid replacement has been optimized.
DHEA
BP= blood pressure; CS= Cushing syndrome; DHEA = dehydroepiandrosterone; IV= intravenous; Na= sodium; K= potassium.
ashorter acting glucocorticoids may be preferred over longer acting agents due to lower risk of glucocorticoid excess. Longer-acting preparations have the advantage of once
daily dosing (see Table 17).
CJ
COH
mineralocorticoid activity. If present. electrolyte abnormali
ties and hypoglycemia should be treated. and precipitants of
replacements for which there has not been a demonstrated
biochemical need.
adrenal crisis (for example. infection) should be sought and
treated. Adrenal Function During Critical Illness
It is critical that patients with suspected primary or sec Glucocorticoid deficiency related to critical illness is an entity
ondary cortisol deficiency and concomitant hypothyroidism that has not been well characterized. It has been postulated that
be treated with glucocorticoids first because correcting thy critical illness may lead to transient pri111ary or secondary cor
roid hormone deficiency will accelerate the clearance of corti tisol deficiency (ACTH deficiency) or an increase in tissue resist
sol and can precipitate acute adrenal crisis. ance to cortisol. The American College of'Critical Care Medicine
In the nonmedical literature. the term ''adrenal Fatigue" recommends considering this diagnosis in patients with hypo
has been used to describe a constellation of symptoms. tension who have responded insufficiently to fluids and vaso
including difficulty sleeping. Fatigue. and salt and sugar pressor therapy. A maximum increase in serum cortisol of
craving. hypothetically from long-term emotional or physi 9 pg/dL (248.4 nmol/L) or less following the administration of
cal stress having a deleterious effect on the adrenal glands , synthetic ACTH has been associated with increased mortality
resulting in a simultaneous excess and deficiency of cortisol . from septic shock: however, results of testing do predict benefit
However. there is no scientific evidence to support this from glucocorticoid therapy. In the setting of' critical illness,
claim. and the term "adrenal Fatigue" should not be used. both CBG and albumin concentrations decrease resulting in
Proponents of adrenal fatigue prescribe synthetic glucocor lower total cortisol . Free cortisol levels. either directly measured
ticoids and supplements containing adrenal, pituitary, or or calculated based on total cortisol and CBC, may be more reli
hypothalamic extracts that can cause iatrogenic CS. as well able in critically ill patients with hypoalbuminemia. It is not
as mineralocorticoid supplements that can lead to hyperten known iffree cortisol levels provide useful prognostic infor111a
sion. Patients should receive appropriate evaluation for their tion. The ad111inistration ofglucocorticoids has not been shown
symptoms and be educated to avoid taking hormonal to benefit critically ill patients who do not have shock. and the
38
Disorders of the Adrenal Glands
Cl
CONT.
results of placebo-controlled randomized trials in patients vvith
septic shock are conflicting. Further research is needed to clar
be undertaken promptly. An algorithm for the evaluation and
follow up of an adrenal mass is shown in Figure 7.
ify if there is a population of critically ill patients who can objec The risk of malignancy varies according to size. OnJy 2%
tively benefit from glucocorticoid therapy. CJ of adrenal masses smaller than 4 cm are cancerous; however,
25'Yo of those larger than 6 cm are malignant. An adrenaJ
mass·s risk of malignancy can be clarified based on its appear
Adrenal Masses ance on CT or MRI (see Table 19 for the typical radiographic
+ Favors Benign:
• Size <4 cm
Suspicious:
• Size >4 cm
+
Functioning tumors:
Tests for Hormone Excessd
• Pheochromocytoma
• Aldosterone-producing adrenal tumor
Follow Up• Cortisol: Aldosterone:
• Subclinical CS with complication(s)9
• Who: All patients • Who: HTN or -.vK+
• Repeat CT or MRI
• Test: LDST • Test: PRA/PAC
at 3-6 months then
annually for 1-2
years
• Repeat hormonal Catecholamines: Androgens:
evaluation annually • Who: All patients • Who: If suspected1
for 4 years
• Test: Plasma or • Test: DHEAS,
urine metanephrines, testosterone,
urine catecholamines• androstenedione
FIGURE 7. Algorithm for the initial diagnostic evaluation and follow up of an incidentally noted adrenal mass. CS= Cushing syndrome; DHEAS= dehydroepiandroster
one sulfate; HTN = hypertension; HU= Hounsfield units; K= potassium; LOST= low-dose (1-mg) dexamethasone suppression test; PAC= plasma aldosterone concentra
tion; PRA = plasma renin activity.
aRepeat imaging c1nd hormone testing are indicated for adrenal masses not meeting crlterio for surgery ot initiol diagnosis.
hRefer to Tobie 19 for more CT and MRI findings. If imaging is suspicious in a patient with known malignancy, biopsy should be considered to confirm adrenal metastasis after screening for pheochromocytoma is completed.
ca scan findings.
dPositive screening tests usually require further biochemical evaluation to confirm the diagnosis {see text).
eMeasure plasma metanephrines if radiographic appearance is typical for a pheochromocytoma; otherwise measure 24·hour urine metanephrines and catecholamines.
1Hormonal evaluation for an androgen.producing adrenal tumor is indicated only if clinically suspected based on the presence of hirsutism, virilization, or menstrual irreguloritles in women.
9Adrenalectomy is considered for confirmed cases of subclinical CS associated with recent onset of diabetes, hypertension, obesity, or low bone mass.
39
Disorders of the Thyroid Gland
40
Disorders of the Thyroid Gland
There are two forms of active thyroid hormone: thyrox range. During pregnancy, the range shifts lower and varies by
ine (T) and triiodothyronine (T/ Iodine is necessary for the trimester (see Thyroid Function and Disease in Pregnancy).
formation of thyroid hormone. Deficiency may result in The second important exception is in the elderly. With aging,
hypothyroidism. The hypothalamic-pituitary-thyroid axis the reference range shifts higher; the upper limit of normal
responds to the subsequent hormone deficiency by increasing extends to 7 µU/mL (7 mU/L) in patients older than 70 years.
thyroid-stimulating hormone (TSH) secretion, resulting in The third exception is in patients with known pituitary dys
development of a goiter. Iodine is typically obtained through function or a risk of pituitary dysfunction (history of cranial
diet; it is present in seafood, dairy products, and iodized salt. irradiation, pituitary surgery, or massive head trauma).
Although iodine deficiency is a worldwide health problem, it If the serum TSH level is frankly abnormal, additional
is relatively rare in the United States with the incorporation of evaluation of thyroid function should be considered to deter
iodine into salt. mine the extent of the dysfunction. This is accomplished by
Thyroid hormone production is controlled by two main measuring T., when the TSH is elevated and by measuring T,1
forces: secretion of TSH (thyrotropin) and regulation of and Ti when the TSH is suppressed.
peripheral conversion of T. 1 to T3 • TSH release from the anterior When indicated by an abnormal TSH, the circulating level
pituitary is stimulated by decreases in concentrations of serum of thyroid hormone should be assessed using total or free T4
T4 and T3 and secretion of thyrotropin-releasing hormone levels. Total T. 1 is a reflection of the bound and unbound frac
(TRH) from the hypothalamus. The T3 and T." in turn, decrease tions of the hormone and is a reasonable method of assessing
secretion of TSH from the anterior pituitary as part of a nega overall thyroid hormone levels in most patients. However, in
tive feedback loop. Additionally, T3 inhibits further secretion of patients with disorders of protein metabolism, such as kidney
TRH from the hypothalamus. or liver disease, measurement of free T,1 ensures a more accu
Although the thyroid gland produces both T3 and T.I' the rate representation of the hormone concentrations.
ratio of T4 to T3 secretion is nearly 20:1, with most T3 (80%) Additionally, conditions that raise serum total protein level,
resulting from 5'-deiodination of T,1 in peripheral tissues. such as in patients taking estrogen or during pregnancy, may
The vast majority of both hormones are bound to circulat result in a higher total T., concentration, and measuring the
ing proteins, including thyroxine-binding globulin, trans free T. 1 is indicated. The same rules apply to T3 as to T,1 regard
thyretin, albumin, and lipoproteins. The function of these ing protein levels, but free T3 has a very short half-life and
proteins is to increase the circulating pool of hormone by levels fluctuate more and are less reliable; therefore, it is con
delaying clearance and maintaining a reservoir of hormone troversial whether total or free T3 should be measured in
available for use. Only a small percentage of total circulating patients at risk for protein abnormalities.
thyroid hormone is free (unbound); this fraction is readily Measurement of serum T3 is necessary if the patient has a
available for cellular uptake and determines the biologic activ suppressed TSH level because, in some patients with thyro
ity of the hormone. toxicosis, T3 may be preferentially secreted over T,1 (T3 toxico
sis). In patients with an elevated TSH level, indicating
KEY POINT
hypothyroidism, measurement of serum T 3 is not helpful
• Thyroid hormone production is controlled by two main because it will be maintained in the normal range even in
forces: secretion of thyroid-stimulating hormone (thy those with significant disease.
rotropin) and regulation of peripheral conversion of Thyroid autoantibody measurement may be helpful
thyroxine (T4) to triiodothyronine (T). under certain clinical circumstances. In patients with a
personal history of autoimmune disease (such as type 1
diabetes mellitus, systemic lupus erythematosus, or celiac
Evaluation of Thyroid Function disease) or a strong family history of thyroid dysfunction,
In patients with an intact hypothalamic-pituitary axis, the measuring thyroid autoantibodies may indicate the cause of
initial laboratory test of thyroid activity is TSH measurement, the thyroid dysfunction or whether a patient is at risk for
which is exquisitely sensitive for detection of disorders of thy developing thyroid autoimmune disease if the TSH is nor
roid dysfunction. In patients for whom there is a high suspi mal. There is no clinical indication for serial measurement
cion of thyroid or pituitary dysfunction, a concomitant thyroid of thyroid antibody titers to determine the need for or to
hormone (T4) level should be assessed with the TSH level to guide therapy. There are three forms of thyroid autoanti
evaluate for central hypothyroidism. The TSH level may reflect bodies: thyroid peroxidase (TPO), thyrotropin receptor
hypofunction (high TSH). hyperfunction (low TSH), or a nor (TRAb), and thyroglobulin (TgAb). Elevated titers of TPO
mal range. antibodies are associated with autoimmune hypothyroid
The normal reference range for TSH is variable among ism, or Hashimoto disease. Patients with TPO antibodies
laboratories but is generally between 0.5 and 5 µU/mL (0.5- and normal thyroid function tests are at an increased risk of
5 mU/L), and determinations of normal TSH levels should be developing overt thyroid failure (2%-4 "lo per year).
made based on the reference range of the laboratory being Thyrotropin receptor antibodies (TRAb) are divided into
used. There are three very important exceptions to this general three types: blocking (also called thyrotropin-binding
41
Disorders of the Thyroid Gland
42
Disorders of the Thyroid Gland
43
Disorders of the Thyroid Gland
If ophthalmopathy is present, the patient may exhibit lid should be withheld for S to 7 days before the administration of
retraction (lid lag), whereby contraction of the levator palpe radioactive iodine therapy. If a patient has a particularly large
brae muscles of the eyelids results in immobility of the upper goiter with compressive symptoms or if there is concern for
eyelid with downward rotation of the eye. Additionally, malignancy, surgery is recommended as first-line therapy.
patients may have proptosis, scleral injection, and periorbital KEY POINT
edema.
Because thionamide drugs also have an immunomodula • Radioactive iodine ablation or surgery is the most com
tory effect that reduces autoantibody titers, antithyroid drugs mon treatment for toxic thyroid nodules; indications for
are often first-line treatment for Graves disease. Up to SO% of surgery include a large goiter with compression symp
patients may go into remission within 24 months, and some toms or concern for malignancy.
may maintain a euthyroid state without further therapy after an Destructive Thyroiditis
initial treatment with thionamides. If the patient does not go Thyroiditis is a selt�Limited inflammatory condition of the thyroid
into remission or if disease recurs, definitive therapy with radi resulting in the release of preformed thyroid honnone into the
oactive iodine ablation or surgery is recommended. However, in circulation. The dmation of the thyrotoxic phase is typically 2 to
patients with Graves ophthalmopathy, there is an acute escala 6 weeks, during which patients may exhibit classic symptoms of
tion of thyroid autoantibody titers following radioiodine ther thyrotoxicosis. Following the release of preformed hormone, the
apy that may exacerbate ocular symptoms. Such patients may
damaged thyroid ceases production ofT3 andT4 dming the recov
be better treated with thionamjdes and/or surgery. ery phase; consequently, administration of thionamides will not
be effective in treating elevated horn1one levels. The patient may
Toxic Adenoma and Multinodular Goiter
then become clinically hypothyroid, a condition that may require
Activating mutations in the TSH receptor gene are responsible
tempora1y levothyroxine therapy. The length of the hypothyroid
for the autonomous production of thyroid hormone in a toxic
phase can va1y but classically is 6 to 12 weeks.
nodule (adenoma) or in multiple hyperfunctioning nodules in
There are two categories of thyroiditis: painful and painiess.
a toxic multinodular goiter. Because of this loss of normal
The causes of painful thyroiditis are inflammatory (de Quervain
regulation of thyroid hormone production, patients are at risk
or subacute granulomatous thyroiditis), infectious (suppurative),
for developing acute thyrotoxicosis when exposed to iodine
and radiation-induced. The pain, typically only present during
excess, particularly after a contrast load for medical testing
the thyrotoxic phase, can be quite intense. Treatment is aimed at
(Jod-Basedow phenomenon), such as in cardiac catheteriza
controlling inflammation with NSAIDs or systemic glucocorti
tion and contrast-enhanced CT scans. Although patients with
coids if severe. Subacute thyroiditis is the most common form
a toxic adenoma or multinodular goiter may exhibit the typi
and is presumably caused by a postviral inflammatory process;
cal symptoms of thyrotoxicosis, they can be relatively asymp
many patients report a recent history of upper respiratmy illness
tomatic. On physical examination, a nodule may be palpable
preceding the thyroiditis. Radiation thyroiditis may occur s to
or there may be a diffusely enlarged goiter with a nodular
10 days after treatment with radioactive iodine. This may be
contour but no discrete palpable nodules.
lf a patient is suspected of having a toxic nodule, thyroid associated with transient exacerbation of the hyperthyroidism.
The accompanying pain is usually mild and lasts for up to 1 week.
scintigraphy should be performed to determine if the nodule
Infectious thyroiditis is rare but may be seen in an immunocom
is autonomous. The thyroid uptake scan will reveal increased
promised patient; the most common causative organisms are
activity in the "hot" nodule with relative suppression of the
Staphylococcus and Streptococcus species.
remaining thyroid tissue. These results should then be corre
Painless thyroiditis is more commonly seen than painful
lated with the ultrasonographic findings to determine if any
thyroiditis and has several causes, including postpartum thy
additional nodules exist, which will require further investiga
tion with FNA. roiditis, silent thyroiditis, and drug-induced thyroiditis.
Radioactive iodine ablation or surgery is the most com Postpartum thyroiditis may occur up to 1 year after delivery;
mon treatment for toxic nodules. Thionarnides can be used to the frequency is variably reported but may occur in up to 10%
decrease hormone production in the short term, but unlike of pregnancies. The presence of TPO antibodies is nearly uni
Graves disease, this condition has no chance of spontaneous versal, and the likelihood of subsequent permanent hypothy
remission and would require lifelong medical therapy, which roidism is ve1y !ugh. Thyroiditis is also likely to recur in later
is not recommended. Radioiodine therapy will ideally ablate pregnancies.
only the autonomous areas. In elderly patients, those with KEY POINT
coronary disease, those who are highly symptomatic, and • Thyroiditis is a self-limited inflammatory condition of
those with severe thyrotoxicosis, thionamides are recom the thyroid resulting in the release of preformed thyroid
mended to normalize thyroid hormone levels prior to radioac hormone into the circulation; the duration of the thyro
tive iodine; this is done to avoid exacerbation of the toxic phase is typically 2 to 6 weeks, which is followed
thyrotoxicosis due to release of preformed hormone from the by a hypothyroid phase typically lasting 6 to 12 weeks.
gland acutely after radioactive iodine ablation. Thionamides
44
Disorders of the Thyroid Gland
Central Hyperthyroidism trauma, pituitary surgery, or cranial radiation can cause cen
TSH-secreting pituitary adenomas are extremely rare. In this tral hypothyroidism.
condition, serumTSH is detectable or normal in the setting of The clinical manifestations of hypothyroidism include
an elevatedT4 and/or T3 concentration. A dedicated pituitary fatigue, cold intolerance, constipation, heavy menses, weight
MRI will demonstrate an adenoma.Treatment should focus on gain, impaired concentration, dry skin, edema, depression,
removal of the pituitary tumor; thyroid-targeted therapy is mood changes, muscle cramps, myalgia, and reduced fertility.
ineffective (see Disorders of the Pituitary Gland). The physical examination findings may include reduction in
basal temperature, diastolic hypertension, bradycardia, dry
Subclinical Hyperthyroidism skin, brittle hair, hoarseness, delayed relaxation phase of the
Subclinical hyperthyroidism is a laboratory-based diagnosis, deep tendon reflexes, and an enlarged thyroid.
defined as the presence of a suppressedTSH level with normal An elevated serum TSH level indicates the diagnosis of
T 3 andT4 levels. Repeat assessment of thyroid function should primary hypothyroidism. ln patients with an elevated TSH
be performed 6 to 12 weeks after the initial tests, as the values that is less than 10 µU/mL (10 mU/L), a low serumT 4 measure
will normalize in up to 30% of patients. Symptoms of thyro ment is helpful, as a frankly low value indicates that thyroid
toxicosis are typically mild; most patients are asymptomatic. hormone replacement is necessary.The presence ofTPO anti
Which patients will benefit most from normalization of bodies suggests that Hashimoto thyroiditis is the underlying
theTSH level is not universally agreed on, but consensus opin cause.Thyroid imaging is not indicated unless there is concern
ion recommends treatment for patients with aTSH level below for a nodule on physical examination.
0.1 µU/mL (0.1 mU/L).The benefits of treatment for asympto KEY POINTS
matic patients with aTSH level between 0.1 µU/mL (0.1 mU/L)
• An elevated serum thyroid-stimulating hormone level HVC
and the lower limit of the normal reference range are less clear.
Emerging data suggest that chronic subclinical hyperthyroid indicates the diagnosis of primary hypothyroidism; thy-
ism has a negative effect on cardiac function, the central nerv roid imaging is not indicated unless there is concern for
ous system, and bone mass. The risk of atrial fibrillation is a nodule on physical examination.
significantly increased when theTSH level is below 0.3 µU/mL • The most frequent cause of primary hypothyroidism is
(0.3 mU/L), so patients over the age of 65 years and those with Hashimoto thyroiditis (chronic lymphocytic thyroidi
a history of coronary artery disease or tachyarrhythmias, as tis); the presence ofTPO antibodies is suggestive of
well as patients with osteoporosis, may benefit from normali Hashimoto thyroiditis.
zation of theTSH level. Radioiodine is the preferred treatment,
but often the gland does not have sufficient iodine avidity and Management
methimazole must be used. In patients with aTSH level greater than 10 µU/mL (10 mU/L),
daily thyroid hormone replacement is recommended.
KEY POINTS
Thyroid hormone replacement with levothyroxine alone
HVC • In patients with subclinical hyperthyroidism, repeat is recommended. The goal of thyroid hormone replacement
assessment of thyroid function should be performed 6 therapy is normalization of the TSH. The starting dose can be
to 12 weeks after the initial tests, as the values will nor weight-based at 1.67 µg/kg/d, using ideal body weight. In
maUze in up to 30% of patients. patients with prevalent cardiac disease, tachyarrhythmias, or
• Treatment for subclinical hyperthyroidism is recom multiple comorbidities, or in those who are older than
mended when the thyroid-stimulating hormone level is 65 years, the dose should not be based on weight but rather
less than 0.1 µU/mL (0.1 mU/L). should be 25 to SO µg/d.The dose should be titrated based on
TSH levels measured 6 to 8 weeks after any dose change. To
improve gastrointestinal absorption, levothyroxine should be
Thyroid Hormone Deficiency taken on an empty stomach, 1 hour before or 2 to 3 hours after
Hypothyroidism ingestion of food or medications that would interfere with
Evaluation absorption, such as calcium- or iron-containing supplements.
Hypothyroidism refers to low circulating thyroid hormone Patients with celiac disease may require higher levothyroxine
levels. Hypothyroidism is more prevalent in women than men doses because of impaired absorption.
(2% versus 0.2%) and in those with other autoimmune dis There has been significant debate regarding the need for
eases. The most frequent cause is Hashimoto thyroiditis, also supplementation of T3 Oiothyronine) in patients with hypo
known as chronic lymphocytic thyroiditis. Iatrogenic causes thyroidism. The short half-life of T3 triggers acute spikes in
include surgery, radioiodine therapy, and external beam radia serum T 3 levels, which are of significant concern for elderly
tion therapy to the neck. Hypothyroidism may also be medica patients or those with preexisting cardiac issues. Additionally,
tion induced; the most common causative agents include numerous studies have failed to show a clear benefit of aT/T3
lithium, amiodarone, interferons, interleukin-2, and tyrosine combination over T4 alone; therefore, this is not generally
kinase inhibitors. Rarely, pituitary tumors, severe head recommended.
45
Disorders of the Thyroid Gland
(10 mU/L), but levothyroxine treatment should be considered • In the majority of patients, amiodarone causes a tempo
in patients who have positive TPO antibodies or a large goiter, rary reduction in circulating triiodothyronine (T) and
as these patients are at risk for progression to overt hypothy thyroxine (T) and levels with a minor rise in the thy
roidism at rates of 3% to 8% per year. A goal TSH level less than roid-stimulating hormone that reverses within first
or equal to 2.5 µU/mL (2.5 mU/L) is recommended for women 3 months of treatment and requires no intervention.
with subclinical hypothyroidism and positive TPO antibody • In 15% of patients, amiodarone may cause either
status who are planning to conceive. hypo- or hyperthyroidism; those at highest risk for
KEY POINT amiodarone-induced hypothyroidism are women with
preexisting thyroid peroxidase antibody positivity.
H If( • In patients with suspected subclinical hypothyroidism,
repeat measurement of the thyroid-stimulating hor
mone level is recommended, as it will normalize in up
to 30% of patients by 6 weeks. Thyroid Function and Disease
in Pregnancy
Drug-Induced Thyroid Dysfunction Significant changes in thyroid function occur during preg
Various medications can affect thyroid function and are listed nancy; understanding the normal physiology during gestation
in Table 26 based on their mechanism of action. is critical for a correct interpretation of thyroid laboratory
Amiodarone may have a potentially toxic effect on the studies. Abnormalities of thyroid function can have a dramatic
thyroid. The iodine content of amiodarone is 37% by weight. It effect on the health of the mother and the fetus. A diagram of
is stored in fat, myocardium, liver, lung, and thyroid tissues, the physiologic changes in thyroid function during each tri
with a half-life exceeding SO days. This long half-life, coupled mester is shown in Figure 8.
with the high iodine content, renders it a potentially toxic Increased estrogen levels cause a rise in thyroxine-bind
compound to the thyroid. The two types of amiodarone thy ing globulin. To maintain a stable free T4 and T3 , thyroid hor
roid toxicity are changes in thyroid function studies seen in all mone production is increased and TSH remains within the
patients (obligatory effects), and those seen in only a subset of normal reference range for the patient's trimester (see later
patients (facultative effects). discussion for trimester-specific ranges). Routine screening of
The obligatory eflects result from the increased circulat TSH is not indicated for every pregnant woman. TSH screening
ing iodine after initiation of the drug. Adaptation to the acute is indicated in women with a risk of thyroid gland dysfunc
iodine excess causes a reduction in organification of iodine tion, including those already on thyroid hormone replacement
f
and reduced production of thyroid hormone (Wolf -Chaikoff therapy; those with autoimmune disorders, goiter, previous
46
Disorders of the Thyroid Gland
Iron
Cholestyrarnine
Aluminum hydroxide
Soybean oil
Sucralfate
Psyllium
Phenobarbital
Sertraline
T hyroiditis Amiodarone May cause hypo- or hyperthyroidism
Lithium
Interferon alfa
lnterleukin-2
Tyrosine kinase inhibitors
De novo development of Interferon alfa May develop Hashimoto thyroiditis, Graves disease, or painless
antithyroid antibodies thyroiditis
Inhibition ofTSH synthesis or Glucocorticoids
release
Dopamine
Dobutamine
Octreotide
Increased thyroxine-binding Estrogen False elevation of total T3, total T 4 levels; free T3,T 4 may be more
globulin accurate reflection of hormone levels
Tamoxifen
Methadone
Decreased thyroxine-binding Androgen therapy False lowering of total T 3, total T 4 levels; free T 3, T4 may be more
globulin accurate reflection of hormone levels
Glucocorticoids
Niacin
head/neck irradiation, previous thyroid surgery, known posi pregnancy, with adjustments in thyroid hormone replacement
tive TPO antibodies or positive TS! antibodies, or a strong fam closing as neeclecl to maintain the TSH within the trimester
ily history of thyroid dysfunction; those who live in sµecific normal range. The largest dose escalations typically
iodine-deficient areas; or those older than 30 years. In patients occur in the first trimester, with more dose stability later in
on Ievothyroxine replacement, the dose of the medication may pregnancy.
need to be increased, on average by 30% to 50%, and µatients Diagnosing possible hyperthyroidism during pregnancy
should have their TSH level checked as soon as a pregnancy may be challenging because some physiologic changes during
test is µositive. gestation may overlap with symptoms of thyrotoxicosis, such
Fetal thyroid tissue is not functional until 10 to 12 weeks' as tachycardia, fatigue, and heat intolerance. Serum TSH and
gestation, necessitating maternal thyroid hormone transfer human chorionic gonadotropin have a common a-subunit,
through the placenta. Thyroid hormone deficiency can nega allowing cross-reactivity at the TSH receptor. Consequently,
tively affect fetal neurocognitive development. It is critical to TSH declines during the first trimester; the reference range
maintain a euthyroid state during pregnancy in these patients. shifts down to 0.03 to 2.5 µU/mL (0.03-2.5 mU/L). During the
TSH testing should be performed every 6 weeks throughout second and third trimesters the upper limit of TSH rises to
47
Disorders of the Thyroid Gland
Cl Euthyroid Sick Syndrome cies requiring critical care. Failure to make a timely diagnosis
and institute treatment is associated with a high mortality rate.
l:uthyroid sick syndrome (ESS). nonthyroidal illness synclmme.
ur lowT, syndrome arc ,·arious 11c1mcs that have been assigned Thyroid Storm
lO the chc1ngcs seen in thyroid function test results during criti Thyroid storm is a severe manifestation or thyrotoxicosis with
cJl illness. Although not a true syndrome. there are signilkant life threatening secondary systemic decompensation (shock).
48
Disorders of the Thyroid Gland
Cl The cardinal features for diagnosis include elevated tempera bleeding. or metabolic derangements. Cold exposure appears
ture, significant tachycardia. heart failure. gastrointestinal dys to be a risk factor. as this condition is more commonly seen in
CONT. . . .
f unction
· (nausea, vom1tmg, ct·1arrhea. and/ or Jaunct·ice). and the winter months.
neurologic disturbances. The range of central nervous system Mental status changes and hypothermia are the most
manifestations includes increasing agitation. emotional !ability, common clinical manifestations. The spectrum of mental sta
confusion, paranoia. psychosis, or coma. Although thyroid tus changes includes lethargy. stupor. coma. depression. or
storm has been reported with many causes of thyrotoxicosis. it even psychosis. Hypothermia (temperature less than 34 .4 °C
occurs most commonly with Graves disease. Thyroid storm [94.0 °F]) is present in nearly .111 patients: lower temperntures
may be precipitated by another event such as infection. surgery. are associated with a worse prognosis. Ventilatory drive is
myocardial infarction. trauma, or part1.1rition. Administration decreased. resulting in hypoxemia ancl hypercapnia. Additional
of radioactive iodine therapy to a patient with untreated or signs include bradycardia. hypoglycemia. hyponatremia. and
uncontrolled hyperthyroidism can trigger thyroid storm. or hypotension. A significant percentage of patients experi
The diagnosis is based on clinical presentation but can ence seizures. which may be related to the coexisting meta
generally be ruled out if T I and T3 levels are within normal bolic derangements.
limits. If myxeclema coma is suspected. the serum TSH and T 1
Treatment of thyroid storm should be directed toward levels should be tested immediately. Diagnosis is macle based
reduction of thyroid hormone production. decreasing peripheral on the clinical presentation and the coexisting metabolic
conversion of T4 to T1 • addressing adrenergic symptoms and abnormalities. The serum cortisol level should be checked as
thermoregulatory changes, searching for and treating precipilat soon as possible to evaluate for concomitant adrenal insum
ing factors, and reversing systemic decompensation. ciency prior to initiation or thyroid hormone replacement.
Thionamides and �-blockers are the mainstay or treatment to While awaiting the results of the serum cortisol measurement.
reduce thyroid hormone production and control adrenergic it is generally advisable to empirically initiate high-dose gluco
symptoms. PTU and propranolol are the preferred agents corticoid therapy. This therapy may be discontinued if the
because they have the added benent or blocking peripheral con serum cortisol level is found to be normal or high.
version of T.1 to T3 • Additionally, high-dose glucocorticoids The lre.1tment or111yxedem.1 coma is aimed at restoration
reduce T.1 conversion to bioactive T3 • At least 1 hour after the first of the euthyroid state with thyroid hor111one therapy. support
dose of a thionamide. iodine drops should be administered to ive care (mechanical ventilation. vasopressors. and glucocorti
inhibit further release of thyroid hormone from the gland. coids). war111ecl intravenous nuids. warming blankets. and
Acetaminophen and cooling blankets may be used to control the management or the underlying precipitating event. The exact
hyperthermia. However. even vvith aggressive therapy and sup close and preparation or thyroid hormone to administer is
portive measures, mo11ality rates are as high as 15% to 20'7.,. Cl controversial: minimal clinical trial information is available to
ascertain the optimal treatment regi111en. It is important to
KEY POINTS
balance the need for rapid reinstate111ent or a euthyroicl state
• Thyroid storm is a severe manifestation of thyrotoxicosis with the risk of precipitating .1 fatal cardiac event due to
with life-threatening secondary systerruc decornpensation increased cardiac work with administration of thyroid hor
(shock); it occurs most commonly with underlying mone. Generally. intravenous levothyroxine therapy is admin
Graves disease coupled with a precipitating factor such as istered. initially as an intravenous bolus or 200 to 500 µg,
infection, surgery, myocardial infarction, or parturition followed by claily closes of SO to 100 µg intravenously until
and mortality is 15% to 20%. transition to an oral formulation is feasible. Treatment with T 1
• In addition to supportive ca.re and treating the partici is not recommended.
pating cause, thionamides and �-blockers are the main Even with aggressive therapy. the mortality rate for 111yx
stay of treatment to reduce thyroid hormone production edema coma is 20'Y., to 25%. Cl
and are often combined with iodine drops and high
KEY POINTS
dose glucocorticoids to treat thyroid storm.
• Myxedema coma is an extreme but rare manifestation
Cl Myxedema Coma
Myxedema coma is an extreme but rare manifestation orhypo
of hypothyroidism, resulting in life-threatening second
ary systerruc decompensation and a mortality rate of
thyroidism, resulting in life-threatening secondary systemic 20% to 25%.
decompensation. Without a frankly low T I level. myxedema • The treatment of myxeclema coma is aimed at restoration
coma is unlikely. regardless of the degree of TSH elevation. 11 of the euthyroicl state with thyroid hormone therapy,
has a very high mortality rate if there is a delay in treatment. supportive care (mechanical ventilation, vasopressors,
Myxedema coma is more common in elderly women: it may and glucocorticoids), warmed intravenous fluids,
occur in those with a history of hypothyroidism or no ante warrrung blankets, and management of the underlying
cedent illness. Precipitating events are frequent, such as myo precipitating event.
cardial infarction, infection. stroke. trauma. gastrointestinal
49
Disorders of the Thyroid Gland
Structural Disorders a neck ultrasound that includes evaluation of the thyroid and
cervical lymph nodes.
of the Thyroid Gland Nodules are frequently detected incidentally on imaging
Thyroid Nodules sh1dies performed for other reasons. The diagnostic evaluation
Nodularity of the thyroid is extremely common; large popula of incidentally discovered thyroid nodules is identical to those
tion studies suggest that up to 5% of women and 1% of men that are clinically detected, with the same rate of malignancy.
have a clinically evident nodule. The prevalence increases with Nodules incidentally identified on fluorodeoxyglucose-PET
age. In autopsy series and screening ultrasound studies , nod (FOG-PET) scanning, however, have a malignancy rate of30%
ules may be seen in up to 60%. to 50%. Consequently, FOG-avid nodules found on PET scans
The differential diagnosis for a nodule in the thyroid is require heightened suspicion and a lower threshold for inter
varied and includes both primary thyroid disorders and meta vention or diagnostic evaluation.
static spread from other primary malignancies (Table 27). Most A careful history should be performed in patients with a
thyroid nodules are benign, with only approximately 10% thyroid nodule. Increased risk of malignancy is found in
harboring a malignancy. Ultrasonography is an inexpensive patients with history of radiation exposure to the head or
and highly effective method for stratification of malignancy neck, a family history of thyroid cancer, or a personal history
risk. All patients with a suspected thyroid nodule should have of thyroid cancer. Additional factors that increase the risk for
malignancy in a nodule include male sex, extremes of age (<20
or >60 years), rapid nodule growth, and hoarseness. On phys
TABLE 27. Types ofThyroid Nodules ical examination, the nodule should be assessed for texture,
Benign Malignant mobility, and associated lymphadenopathy. If the nodule is
hard, fixed to surrounding tissue (nonmobile with swallow
Multinodular goiter Papillary thyroid cancer
(colloid adenoma)
ing), and/or there is associated cervical lymphadenopathy, the
risk of malignancy is greater. Pain is an uncommon finding
Hashimoto (chronic Follicular thyroid cancer
lymphocytic) thyroiditis
with thyroid nodules, but when present it is usually associated
with benign conditions.
Colloid cyst Medullary thyroid cancer
A serum TSH measurement is the initial laboratory test in
Hemorrhagic cyst Anaplastic thyroid cancer
a patient with a thyroid nodule. If the TSH is suppressed,
Follicular adenoma Primary thyroid lymphoma measurement ofT4 and T3 should be performed, and a radio
Hurthle cell adenoma Metastatic cancer nuclide scan should be considered (Figure 9). The objective of
Breast the scan is to identify "hot" or functioning nodules, which
Melanoma
have a very low likelihood of malignancy and typically do not
require FNA. In contrast, if the TSH is high or normal, the
Renal cell
radionuclide scan is unnecessary as it is unlikely to reveal a hot
.----1�
Ultrasound Thyroid scan, FT,, FT,
NoFNA Evaluate
Treat hyperthyroidism for US-guided FNA
FIGURE 9. Initial evaluation of a thyroid nodule. There are size thresholds for FNA based on US appearance. A less suspicious lesion may not need FNA until it is larger
than 2 cm, suspicious nodules if larger than 1 cm. FNA= fine-needle aspiration; FT 3 = free triiodothyronine; FT 4 = free thyroxine; TSH = thyroid-stimulating hormone; US=
ultrasound.
50
Disorders of the Thyroid Gland
nodule; the evaluation should proceed with an ultrasound and Nodules that are benign by FNA should be followed with
possible FNA. As thyroid nodular disease can be altered by repeat ultrasound examination in 6 to 18 months to assess for
normalization of the TSH, ultrasound andFNA should be post significant changes. lf the nodule is stable on repeat imaging
poned in patients with elevated TSH until TSH is normal, and lacks suspicious features, clinical examination and repeat
unless there is marked concern for malignancy. One-time ultrasound can be extended to longer intervals, such as 3 to
measurement of thyroid antibodies may be appropriate if S years. Greater than SO% change in nodule volume or interval
autoimmune thyroid disease is suspected or if muitinoduiar development of concerning ultrasound characteristics should
goiter is identified by ultrasound to stratify the patient's future prompt a repeat FNA to evaluate for a false-negative initial
risk of developing overt thyroid failure. Serum thyroglobulin biopsy.
measurement is not useful and is not recommended. Malignant nodules and those that are suspicious for
FNA, performed under ultrasound guidance, is the opti malignancy require prompt excision; this is typically done
mal test to determine whether a nodule is malignant. When with total thyroidectomy, but hemithyroidectomy may be
performed by an experienced clinician, FNA is safe and rela preferable for patients younger than 45 years of age with a
tively simple to perform. The sensitivity ofFNA cytology is 90% tumor smaller than 4 cm. A nondiagnostic FNA warrants a
to 95%, and the false-negative rate is 3% to 5%. FNA of a nodule repeat attempt. ln a solid nodule with two unsatisfactory biop
is generally recommended for those nodules larger than 1 cm sies, diagnostic hemithyroidectomy is indicated. Surgical
that are solid and hypoechoic. The threshold for FNA of nod complications include hypoparathyroidism and recurrent
ules that are partially cystic and lacking suspicious ultrasound laryngeal nerve paresis; although typically temporary, either
features is 2 cm in size or greater. Aspirating a nodule of S mm complication may be permanent in up to 3% of patients.
or more may be considered if a patient has risk factors such as
KEY POINTS
a personal or family history of thyroid cancer or prior radia
tion exposure. • Thyroid nodules are found in 1 % to 5% of the popula
The sonographic appearance of a nodule may be used to tion; most thyroid nodules are benign, with only
assess the risk of malignancy and thereby guide the decision of approximately 10% harboring a malignancy.
which nodules require biopsy. Features concerning for malig • A serum thyroid-stimulating hormone measurement is HVC
nancy include microcalcifications, marked hypoechogenicity, the initial laboratory test in a patient with a thyroid
irregular borders, and taller-than-wide shape. Such findings nodule; if the thyroid-stimulating hormone is sup-
are nearly 70% specific for cancer, but their poor sensitivity pressed, then measurement of thyroxine (T,1) and triio
cannot exclude the presence of malignancy. dothyronine (T3) should be performed, and a radionu-
The various diagnoses obtained on FNA and the associ clide scan should be considered to identify "hot" or
ated risks of malignancy are listed in Table 28. functioning nodules, which have a very low likelihood
of malignancy and typically do not require fine-needle
aspiration.
TABLE 28. Diagnoses Obtained by Fine-Needle • lf the thyroid-stimulating hormone level is high or nor- HVC
Aspiration of Thyroid Nodules and Risk for Malignancy
ma!, the radionuclide scan is unnecessary as it is
FNA Diagnosis Risk for Management unlikely to reveal a hot nodule and ultrasonography is
Malignancy
an inexpensive and highly effective method for stratifi-
Benign <3% Serial ultrasound cation of malignancy risk for nonfunctioning thyroid
examinations for nodules.
growth
• Fine-needle aspiration of a nodule is generally recom
Atypia of uncertain 5%-10% Repeat FNA
significance/follicular mended for those nodules larger than 1 cm (0.4 in) that
lesion of uncertain are solid and hypoechoic and is the optimal test to
significance determine whether a nodule is malignant.
Suspicious for 20%-30% Hemithyroidectomy
follicular lesion
Goiters
Suspicious for 50%-75% Hemithyroidectomy
malignancy or total thyroidectomy Multinodular Goiter
Malignant 97%-100% Total thyroidectomy
Multinodular goiters occur more frequently with advancing
age, low iodine intake, or Hashjmoto disease. The risk for
Nondiagnostic 0%-50% Repeat FNA; if two
nondiagnostic FNAs, malignancy is the same for multiple nodules as it is for a soli
surgery tary nodule; therefore, the evaluation and management are
Modified from: Cibas ES. Ali SZ; NCI Thyroid FNA State of the Science Conference.
identical. Biopsy should be performed on the three or four
The Bethesda System For Reporting Thyroid Cytopathology. Am J Clin Pathol. nodules (larger than 1 cm) with the most suspicious ultra
2009 Nov; 132(5):658-65. [PMID: 19846805]
sound features. In the absence of suspicious features, the larg
FNA = fine.needle aspiration.
est nodules should be chosen for aspiration.
51
Disorders of the Thyroid Gland
A large multinodular goiter may be associated with com the trend, there is evidence that larger tumors are increasingly
pressive symptoms such as dysphagia, hoarseness, or posi being discovered.
tional dyspnea. To assess the extent of mass effect, additional The vast majority of patients with thyroid cancer have
testing and imaging, including noncontrast CT of the neck/ well-differentiated thyroid cancer, with excellent long-term
chest, barium swallow, direct Jaryngoscopy, and/or spirometry survival. The major forms and their relative frequency are
with flow-volume loops, may be indicated. Levothyroxine listed in Figure 10. The most common well-differentiated thy
therapy to suppress TSH secretion and reduce goiter size is roid cancers are papillary, papillary-follicular variant, and
generally not helpful, poses a risk of thyrotoxicosis, and is not follicular. There are rare, less well-differentiated variants of
recommended. Radioactive iodine ablation is not an option for papillary thyroid cancer (columnar, tall cell, insular, oxyphilic,
euthyroid and hypothyroid patients. Surgical removal is the clear cell, diffuse sclerosing) that are more aggressive and
treatment of choice if the compressive symptoms are signifi carry a worse prognosis. Anaplastic thyroid cancer is undif
cant, if malignancy is suspected, or if the patient desires cos ferentiated and is the most aggressive form of thyroid cancer;
metic intervention. 1-year survival rates range from 20% to 30%.
Staging and prognosis of well-differentiated thyroid can
KEY POINTS
cers (papillary and follicular) are based on the American Joint
• In patients with a multinodular goiter, the risk for Committee on Cancer criteria, which include age (<45 or 2:45
malignancy is the same for multiple nodules as it is for years), primary tumor size, local and distant metastases, and
a solitary nodule; therefore, the evaluation and manage capsular and Jymphovascular invasion. However, because the
ment are identical. majority of patients have excellent survival, T (tumor) N (node)
• Surgical removal of a large multinodular goiter is the M (metastasis) staging plays a minimal role in the management
treatment of choice if the compressive symptoms are of thyroid cancers. Instead, decisions regarding treatment are
significant, if malignancy is suspected, or if the patient aimed at lowering the likelihood of recurrent disease.
desires cosmetic intervention. Treatment of well-differentiated thyroid cancer includes
a combination of surgery, radioactive iodine, and levothyrox
Simple Goiter ine suppression. The extent of surgery is largely based on the
A simple goiter is defined as an enlargement of the thyroid tumor size; solitary tumors smaller than 1 cm may be suffi
gland without the presence of nodules. It may be seen in ciently managed with lobectomy alone. Patients with larger
conditions of dyshormonogenesis, autoimmune thyroid dis tumors, multifocal disease, nodal metastases, or a history of
ease, or primary thyroid lymphoma. Primary thyroid lym irradiation are best treated with total or near-total thyroidec
phoma is a rare condition that typically occurs in elderly tomy. For patients younger than 45 years of age with a tumor
women with a history of Hashimoto thyroiditis. The clinical smaller than 4 cm and no evidence of nodal or distant metas
presentation is a symptomatic, rapidly enlarging goiter with tases, hemithyroidectomy may be a reasonable alternative to
a very firm texture. Patients may also have systemic lym total thyroidectomy. The decision to administer radioactive
phoma symptoms and lateral cervical lymphadenopathy. The iodine is based on two factors: improvement in mortality rates
diagnosis can be made by FNA. Treatment typically involves and/or reduction in recurrence risk. Patients with distant
chemotherapy and/or radiation therapy. Surgery generally is metastases have improved survival with successful radioiodine
not indicated, but it can be used to aid in diagnosis when
FNA is not informative.
Thyroid Cancer
The incidence of thyroid cancer is rising at a faster rate than
any other type of malignancy; the incidence has more than
doubled in the last 30 years. This increase is due solely to pap • Papillary
illary cancers, with the highest rate of rise occurring in tumors
• Follicular
measuring less than 2 cm. Meanwhile, the survival rate for
• Medullary
thyroid cancer has remained stable or slightly improved.
• Anaplastic
Autopsy series reveal that occult thyroid cancers measuring
Jess than 1 cm may be identified in as many as 20% of dissected Other (thyroid lymphoma
and metastases from other
specimens. This finding, coupled with the improving survival cancers)
rate, has Jed some investigators to conclude that the change in
incidence of thyroid cancer is due solely to increased inciden
tal detection of indolent tumors because of greater use of FIGURE 1 0. Relative frequency of the types of thyroid cancer.
imaging modalities. Although there is little doubt that esca
Data from Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases
lated detection of otherwise occult tumors has contributed to of thyroid carcinoma treated in the U.S., 1985-1995. Cancer. 1998 Dec 15;83(12):2638-48. IPMID: 9874472]
52
Reproductive Disorders
� 9
therapy may also be used to improve morbidity and reduce �
mortality, particularly in patients with persistent disease or 8 8
distant metastases. The necessary degree of TSH suppression
varies according to the risk of cancer progression and comor
bidities of the patient. Patients with persistent disease typi Theca cells , - - - ->- Granulosa cells
cally require lowering of theirTSH level to less than 0.1 µU/mL
(0.1 mU/L), whereas those who are free of disease but have a
high risk for recurrence should have a targetTSH level ofO.l to Androstenedione Estradiol Ovulation I
0.5 µU/mL (0.1-0.5 mU/L) for 5 to 10 years. Those patients
who are disease-free with a low risk of recurrence should FIGURE 11 . Female reproductive axis. Pulses of GnRH drive LH and FSH pro·
maintain aTSH level of 0.3 to 2.0 µU/mL (0.3-2.0 mU/L). duction. LH acts on theca cells to stimulate androgen (principally androstenedione)
Medullary thyroid cancer represents less than 10% of all production. Androstenedione is metabolized to estradiol in granulosa cells. FSH
acts on granulosa cells to enhance follicle maturation. Granulosa cells produce
thyroid cancers. Approximately 25% of medullary thyroid can inhibin Bas a feedback regulator of FSH production. FSH = follicle-stimulating
cers are hereditary; all patients with medullary thyroid cancer hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone;
should be screened with RET proto-oncogene sequencing. - (circled)= negative feedback.
Medullary thyroid cancer may be associated with several syn
dromes, including multiple endocrine neoplasia type 2A
(MEN2A) (which may include pheochromocytoma and hyper FSH, under control of pulsatile GnRH secretion, rises in the
parathyroidism), MEN2B (marfanoid habitus and mucosa! early menstrual cycle to promote recruitment and growth of a
ganglioneuromas), or familial medullary thyroid cancer (med follicle containing a microscopic oocyte (follicular phase).
ullary thyroid cancer alone). Biochemical screening for pheo Granulosa cells lining the follicle secrete estradiol, which contrib
chromocytoma with measurement of plasma fractionated utes to negative feedback inhibition ofFSH secretion and result
metanephrine levels should be done in all patients with an ant monofollicular development in the majority of women.
RET mutation prior to thyroidectomy. Estradiol also stimulates endometrial proliferation. Further into
the follicular phase, estradiol levels peak and exert acute positive
KEY POINTS feedback on the pituitary gland, which elicits an LH surge.This
• The vast majority of patients with well-differentiated LH surge results in ovulation and initiates the luteal phase of the
thyroid cancer have excellent long-term survival. menstrual cycle. LH stimulates androgen production by the theca
• Treatment of well-differentiated thyroid cancer includes cells, which also line the follicle; androgen is subsequently aro
a combination of surgery, radioactive iodine, and levo matized to estrogen in the granulosa cells via aromatase enzyme.
thyroxine suppression of thyroid-stimulating hormone After the LH surge and ovulation, the follicle develops into the
for patients with persistent disease or high risk of corpus luteurn, which secretes both estradiol and progesterone
recurrence. and causes the secretory phase of the endometriurn in prepara
tion for implantation of a fertilized oocyte. With implantation, the
early embryo produces human chorionic gonadotropin, which
maintains the corpus luteurn. However, when a fertilized embryo
Reproductive Disorders is not present, progesterone levels decline, leading to the men
strual phase of the endometriurn and menstrual bleeding.
Physiology of Female An average menstrual cycle ranges from 25 to 35 days in
Reproduction length. The follicular phase may vary in each woman but is
A regular, predictable menstrual cycle requires coordination typically from 14 to 21 days. Variability in a menstrual cycle is
of inhibition and stimulation between the hypothalamus typically the result of a shortened or lengthened follicular phase,
(secreting gonadotropin-releasing hormone [GnRH]), the more commonly seen during the first 5 years of menstruation.
pituitary (secreting follicle-stimulating hormone [FSH] and A decrease in follicular phase length occurs commonly in peri
luteinizing hormone [LH]), and the ovaries (secreting estra menopause.The luteal phase is usually 14 days and is constant.
diol and progesterone). The coordination of these signals is In women younger than 40 years of age, menstrual cycles less
referred to as the hypothalamic-pituitary-ovarian axis. The than 25 days or greater than 35 days are likely anovulatory.
GnRH pulse frequency varies throughout the menstrual KEY POINT
cycle to promote follicular development and ovulation
• In women younger than 40 years of age, menstrual
(Figure 11). The phases of the menstrual cycle are referred to
cycles less than 25 days or greater than 35 days are likely
in reference to the activity of the ovary (follicular and luteal
anovulatory.
phases).
53
Reproductive Disorders
------ - ---- ---- - ----- ---- -------- -
-
54
Reproductive Disorders
55
Reproductive Disorders
56
Reproductive Disorders
support moving directly to in vitro fertilization treatment for Leydig cell production of testosterone occurs in a diurnal
women with infertility at age 40 years. In women treated pattern, with the highest concentration observed in the morn
with ovarian stimulation, oral medications such as clomi ing. A large percentage of circulating testosterone is bound
phene citrate or Ietrozole are typically used. This therapy is either to SHBG or albumin. A serum total testosterone level
not appropriate in patients with POI. Patients should be measured in the early morning is generally considered to be an
counseled about the 5% to 8% risk of multiple gestation with accurate measurement of a patient's androgen status, but it
these therapies. Referral to a reproductive endocrinologist is does not account for decreased SHBG as seen in obesity (see
recommended. Evaluation of Male Hypogonadism).
KEY POINT
Secondary Hypogonadism
GnRH
Typically secondary hypogonadism is a result of insufficient
GnRH production by the hypothalamus or deficient LH/FSH
secretion by the anterior pituitary. Causes may be congenital
9
8 8 or acquired. Idiopathic hypogonadotropic hypogonadism,
GF
with anosmia (Kallmann syndrome) or without anosmia, is
the most common cause of congenital secondary hypog
onadism. Acquired secondary hypogonadism is most com
Leydig cells Sertol i cells lnhibin B monly iatrogenic due to exogenous testosterone administra
tion. Untreated sleep apnea and obesity are other common
causes. Other acquired causes include hyperprolactinemia,
Testosterone Spermatogenesis I chronic opioid use, glucocorticoid use, or infiltrative disease
(lymphoma or hemochromatosis).
57
Reproductive Disorders
the increased sales of testosterone formulations to treat aging hypogonadotropic state is revealed, transferrin saturation and
men, questions have emerged about the potential adverse ferritin levels should be evaluated to exclude hemochromato
effects of exogenous testosterone therapy, particularly in men sis. MRI of the pituitary should be performed to evaluate for
who have no biochemical evidence of testosterone deficiency. hypothalamic or pituitary masses as the cause of the hypogon
Potential adverse effects include increased risk of cardiovascu adotropic state if no confounding medications or reversible
lar disease and death, venous thromboembolism, and prostate secondary causes are discovered. Figure 13 shows an algorithm
cancer. for evaluating male hypogonadism.
KEY POINTS
58
Reproductive Disorders
Suspect hypogonadism
Elevated PRL level, other pituitary deficiencies Elevated transferrin saturation, ferritin level
Signs/symptoms of mass effect, testosterone level <150 ng/dL
(5.2 nmol/L)
FIGURE 13. Algorithm for evaluating male hypogonadism. FSH = follicle-stimulating hormone; LH = luteinizing hormone; PRL = prolactin;
SHBG = sex hormone-binding globulin; x2 = two separate measurements.
gels). They require daily use and may incur significant cost to rone level should be in the mid-normal range. Monitoring of
the patient, but the steady level of testosterone achieved the prostate specific antigen and hematocrit level should
within 30 minutes of application is an appealing feature. follow Endocrine Society guidelines (Table 29).
Inadvertent absorption by patient contacts may occur; users
KEY POINTS
should be informed that virilization of contacts is not uncom
mon and premature puberty can occur in exposed children. • Testosterone deficiency should be diagnosed biochemi
The patient should also be counseled that decline in endog cally, and its cause should be definitively determined
enous testosterone production and spermatogenesis may before initiation of testosterone replacement therapy.
occur. If fertility is desired, testosterone therapy should be • Patients requiring testosterone replacement therapy
avoided, and consultation with a reproductive endocrinolo should have testosterone, prostate specific antigen, and
gist is recommended. hematocrit levels monitored.
Patients requiring testosterone replacement therapy • Goal total testosterone level should be in the mid
should have testosterone levels monitored at 3 and 6 months normal range for patients requiring testosterone therapy.
after initiation and annually thereafter; the goal total testoste-
59
Reproductive Disor d e r s
60
Calcium and Bone Disorders
with gynecomastia owing to increased aromatase activity in In both cases, ionized calcium should be measured. It will
the periphery. Estrogen-secreting tumors (such as Leydig or usually be normal, indicating normal circulating free levels of
Sertoli cell tumors or adrenal cortical carcinoma) and HCG calcium. There are also instances of artificially increased cal
secreting tumors (such as germ cell tumors and hepatic carci cium levels due to high protein states as in multiple myeloma
nomas) are associated with gynecomastia. (elevated monoclonal immunoglobulins), hyperalbumine
A thorough history should be obtained. The breasts mia, Waldenstrom macroglobulinemia, and thrombocytosis.
should be examined for glandular enlargement, which typi In these patients, ionized calcium would be normal with ele
cally extends concentrically from under the areolae, and is vated total serum calcium.
firm, mobile, and rubbery. The breasts may be tender if the Vitamin D is a fat-soluble vitamin, and body sources
time course is acute. Pseudogynecomastia is subareolar adi include de novo production from the skin, through forms
pose tissue, without glandular proliferation, that is associ found in food, and through supplementation (Table 30). There
ated with obesity. True gynecomastia typically distorts the are two forms of vitamin D supplementation: vitamin D2
normally flat contour of the male nipple, causing it to pro (ergocalciferol) and vitamin D 3 (cholecalciferoi). Although
trude owing to the mass of glandular tissue beneath it. In both forms are useful in raising vitamin D levels, vitamin D 3
pseudogynecomastia, the nipple is typically still flat but soft, may be more beneficial because of tighter bonding to vitamin
and nondescript subcutaneous fat tissue is present in the D receptors, longer shelf life, greater potency than vitamin D 2,
breast area. and being identical to the vitamin D that naturally occurs in
Mild, chronic, asymptomatic gynecomastia does not war humans after ultraviolet light exposure.
rant evaluation. Evaluation of gynecomastia that is asymmet Regardless of the method of ingestion, vitamin D 3 and D 2
ric or concerning for malignancy (bloody nipple discharge, are both inactive forms that must be hydroxylated twice before
hard and fixed, associated with regional lymphadenopathy), of becoming active. The first occurs in the liver and converts
rapid and recent onset, or larger than 2 cm (>5 cm in obese vitamin D to 25-hydroxyvitamin D [25(0H)D], also known as
men owing to the known increase in aromatase activity in calcidiol. The second occurs primarily in the kidney and forms
obesity), should include measurement of total testosterone,
LH, FSH, and TSH levels, as well as assessment of liver and
TABLE 30. Sources of Vitamin D '
kidney function. If indicated by findings on history and/or
physical examination, measurement of prolactin, estradiol, Sources Type of Amount of
Vitamin D Vitamin D
and HCG may also be indicated. If the biochemical evaluation
demonstrates abnormalities, further evaluation with testicular Food Sources
ultrasound, adrenal CT, or pituitary MRI may be indicated; Cod liver oil Cholecalciferol 400-1000 U/
consultation with an endocrinologist is recommended before teaspoon
imaging is ordered. Salmon, wild caught Cholecalciferol 600-1000 U/4 oz
• Unilateral gynecomastia in the male patient is concern Mackerel, canned Cholecalciferol 250 U/4 oz
ing for malignancy and warrants immediate evaluation Sundried shitake Ergocalciferol 1600 U/4 oz
with a mammogram. mushrooms
Fortified Foods
61
Calcium and Bone Disorders
l
KEY POINTS
Skin • Classic symptoms of hypercalcernia are polyuria, poly
dipsia, anorexia, nausea, abdominal pain, constipation,
and mental status changes; as serum calcium levels
7-Dehydrocholesterol
increase and/or the rate of change increases, symptoms
become more severe, with profound mental status
Cholecalciferol
(vitamin D3) changes, obtundation, and acute kidney injury.
• 25-Hydroxyvitamin D has a relatively long half-life of HVC
several weeks, is the best indicator of whole body
vitamin D status, and is the recommended test for
Dietary Sources of Vitamin D
Cholecalciferol D3 (fish, meat) vitamin D deficiency.
Ergocalciferol D 2 (supplements)
62
Calcium and Bon e Disord ers
200
180
160
� 140
Primary hyperparathyroidism
120
100 Vitamin D
deficiency
80
60
Normal
40
20 Hypoparathyroidism
Hypercalcemia of malignancy
0
6 7 8 9 10 11 12 13 14 15
FIGURE 1 5. Relationship of calcium, PTH, and vitamin D status in normal conditions and in several diseases. PTH = parathyroid hormone.
63
Calcium and Bone Dis orders
TABLE 32. Indications for Surgical Intervention in Patients benign primary hyperparathyroidism, parathyroid carcinoma
with Primary Hyperparathyroidism is equally prevalent in both sexes, more commonly presents
with kidney and bone involvement and a neck mass, and fre
Increase in serum calcium level �1 mg/dL( 0.25 mmol/L) above
upper limit ofnormal• quently is associated with a total serum calcium level greater
than 14 mg/dL (3.5 mmol/L) and very high parathyroid hor
Creatinine clearance must be <60 mUmin (0.06 Umin)•
mone levels, typically greater than four times the upper limit
T-score (on DEXA scan) of-2.5 or worse at the lumbar spine,
total hip, femoral neck, or distal radius• of normal. Most patients present with single gland involve
ment. Because parathyroid carcinomas may not appear histo
Age 50 years or younger•
logically different from benign adenomas, local spread from
Surgery also indicated in patients in whom medical surveillance the capsule, distant metastasis, or lymph node involvement
is neither desired nor possible, including those with significant
bone, kidney, gastrointestinal, or neuromuscular symptoms must be present for carcinoma diagnosis. In these patients,
typical of primary hyperparathyroidism surgical resection is the treatment of choice with calcimimet
DEXA = dual-energy x-ray absorptiometry. ics used for residual disease or in patients who are poor surgi
.:i1n otherwise asymptomatic patients.
cal candidates. Any patient found to have parathyroid carci
noma should be screened for the HRPT2 gene, and if positive,
Recommendations from Bilezikian JP, Khan AA, Potts JT Jr. Third International
Workshop on the Management of Asymptomatic Primary Hyperparathyroidism. family members should be screened as well.
Guidelines for the management of asymptomatic primary hyperparathyroidism:
summary statement from the Third International Workshop. J Clin Endocrinol
Metab. 2009 Feb;94(2):335-9 IPMID: 191939081
Tertiary Hyperparathyroidism
Tertiary hyperparathyroidism is the result of the prolonged
PTH stimulation needed to maintain normocalcemia resulting
In patients with osteoporosis who are poor surgical can from decreased 1,25-dihydroxyvitamin D levels from kidney
didates or refuse surgery, intravenous bisphosphonate therapy impairment. This prolonged stimulation results in increased
will slow bone resorption and temporarily decrease serum calcium levels and severe hyperparathyroid hyperplasia and
calcium levels. Intravenous bisphosphonate should be redosed elevated PTH levels that do not respond to phosphate binders
when hypercalcemia recurs. and calcitriol therapy. Severe bone loss and other symptoms
In patients who do not meet the criteria for surgery, sur make surgical resection the treatment of choice.
veillance is recommended. Patients should have annual meas
urement of serum calcium and creatinine levels. A three-site Normocalcemic Primary Hyperparathyroidism
dual-energy x-ray absorptiometry (DEXA) scan should be Normocalcernic primary hyperparathyroidism is defined as
performed every 1 to 2 years to evaluate bone mineral density increased PTH levels in the absence of elevated calcium levels.
of the lumbar spine, hip, and distal radius. The frequency of This is a diagnosis of exclusion used in patients being evalu
DEXA scanning should increase to yearly when any treatment ated for low bone density in which all secondary causes have
has been initiated for bone health or other medications have been ruled out, including vitamin D deficiency. Approximately
been added that may affect bone health (antiandrogen, anties 20% of these patients will develop hypercalcemia within
trogen , antiseizure medications, or glucocorticoids). 3 years, so they should be monitored closely.
In patients with asymptomatic primary hyperparathy
roidism, other precautions can be taken to prevent disease Familial Hypocalciuric Hypercalcemia
related complications. These patients should maintain The most common form of familial hypercalcernia is familial
adequate vitamin D (400-600 U daily) intake to prevent fur hypocalciuric hypercalcemia (FHH). It is a rare autosomal dom
ther PTH stimulation. In patients with concomitant vitamin D inant condition with a high penetrance that often occurs in
deficiency, repletion is recommended to replete patients childhood. These patients are frequently asymptomatic, but in
whose levels are below 30 ng/dL (75 nmol/L) with careful rare cases the calcium-sensing receptor (CASR) gene mutation
attention to urine calcium excretion and serum calcium once can increase the risk of pancreatitis. Elevated serum calcium
values are greater than 30 ng/dL (75 nmol!L). A large study did levels are caused by a mutation in the G-coupled protein CASR
not show worsening calcium levels when repleting vitamin D gene. These receptors are in the parathyroid glands and the kid
in patients with levels less than 30 ng/dL (75 nmol/L)_ neys. The sensor mutation results in a shift upward in the "nor
Adequate physical activity to prevent bone resorption and mal" range of calcium that the receptor recognizes, resulting in a
adequate hydration to prevent kidney damage are imperative. mildly elevated serum calcium level (usually less than 11.0 mg/
dL [2.8 mmol/L]) and high normal or mildly elevated PTH level.
Parathyroid Carcinoma An elevated PTH level is more commonly seen in patients with
Parathyroid carcinoma is very rare, accounting for less than 1 "lo concomitant vitamin D deficiency. The diagnosis is made by
of all persons with primary hyperparathyroidism. Mutations measuring 24-hour urine calcium excretion levels. Typically,
in the HRPT2 gene are thought to be the major genetic link in patients with FHH will have a 24-hour urine calcium level less
parathyroid carcinoma, and inactivation of this gene leads to than 200 mg/24 h (5.0 mmol/24 h). The preferred standard is the
familial hyperparathyroidism as well. When compared with calcium-creatinine clearance ratio, using the following formula:
64
Calcium and Bone Disorders
Ca/Cr clearance ratio= [24-hour urine Ca x serum Cr] � [serum hypercalcemia through increased bone resorption.
Ca x 24-hour urine Cr]. A ratio less than 0.01 confirms the diag Resolution of the thyrotoxicosis should lead to normaliza
nosis if all other causes of hypocalciuria (thiazides, lithium, tion of calcium levels. Prolonged immobilization and
vitamin D deficiency) have been excluded. FHH is usually a increased vitamin A levels can lead to increased bone
benign condition that requires no intervention but should be resorption. Increased levels of calcium absorption from the
recognized to prevent unnecessary parathyroidectomy. gut can be from markedly high vitamin D levels or increased
intake of calcium carbonate products (milk-alkali syn
Other Familial Hypercalcemias drome). Granulomatous diseases, such as sarcoidosis and
Familial hyperparathyroidism is another rare cause of hyper Wegener granulomatosis, and malignant lymphomas cause
caicemia. The disease presentation is almost identical to spo hypercalcemia through increased I-a-hydroxylation activ
radic primary hyperparathyroidism, and a careful family his ity that increases 1,25 -dihydroxyvitamin D levels and cal
tory will suggest the diagnosis. Once a diagnosis of primary cium reabsorption in the gastrointestinal tract.
hyperparathyroidism is made, screening for familial causes
should be done if the patient (1) is younger than 30 years of age Treatment of Hypercalcemia
at the time of diagnosis, (2) has a family history of hypercalce The treatment of hypercalcemia should focus on decreasing the
mia, or (3) has a medical history of other endocrinopathies. serum calcium level by increasing calcium excretion and
These patients should be tested for multiple endocrine neopla decreasing bone resorption or intestinal calcium absorption, as
sia syndrome types 1 and 2 (MENl and MEN2). well as volume repletion. Polyuria, due to the decreased concen
MENl is characterized by functional pituitary adenoma, tration ability of the distal tubule, is the main cause of dehydra
functional pancreatic tumors, and primary hyperparathyroidism. tion in these patients. Although many patients do not require
MEN2A is characterized by medullary thyroid cancer, pheochro hospitalization, those with marked mental status changes, acute
mocytoma, and parathyroid gland hyperplasia with the associ kidney injury, or calcium levels greater than 12 mg/dL (3 mmol!L)
ated RET oncogene mutation. Patients with MEN would follow should be hospitalized for treatment. First-line therapy is aggres
similar guidelines for surgical removal of parathyroid glands. sive intravenous fluid resuscitation. Once the patient is volume
replete, an intravenous loop diuretic should be added if the cal
Medications Causing Hypercalcemia
cium level has not normalized. Intravenous bisphosphonate
Thiazide diuretics decrease the reabsorption of calcium in the
therapy is usually given for longer-term control of hypercalce
kidney and result in elevated levels. Primary hyperparathy
mia. Caution should be exercised with these agents in the setting
roidism, however, should also be considered if the patient
of kidney dysfunction. Zoledronic acid, while more expensive, is
remains hypercalcemic despite the discontinuation of the thi
a more effective therapy for patients with malignancy-related
azide diuretic. In these patients, the thiazide may have been
hypercalcemia. In patients resistant to or intolerant of bisphos
masking the PTH-mediated hypercalcemia.
phonate therapy, off-label use of denosumab, which also reduces
Lithium decreases the parathyroid glands' sensitivity to
osteoclast-mediated bone resorption can be used. Attention
calcium and may also reduce urine calcium excretion.
should be turned as quickly as possible to treatment of the
Non-Parathyroid Hormone-Mediated Hypercalcemia underlying cause of the patient's hypercalcemia to ensure long
In contrast to PTH-mediated hypercalcemia, non-PTH term maintenance of normocalcemia. If the underlying cause is
mediated hypercalcemia is associated with very low PTH lev increased 1,25-dihydroxyvitamin D hydroxylation, glucocorti
els, typically less than 10 to 15 pg/dL (10-15 ng/L). coids can be effective therapy but may need to be dosed on a
regular basis. For patients who present with serum calcium
Malignancy-Associated Hypercalcemia levels greater than 18 mg/dL (4.5 mmol/L) with neurologic
There are two mechanisms of hypercalcemia of malignancy: symptoms or compromised kidney function, hemodialysis is an
local osteolytic and humoral. When lytic bone metastases are appropriate choice to quickly reduce calcium levels.
present, hypercalcemia is the result of increased mobilization
KEY POINTS
of calcium from the bone. Humoral hypercalcemia is less com
mon and occurs when the tumor itself produces parathyroid • Primary hyperparathyroidism is the most common
related protein (PTHrP) that binds to and activates the cause of parathyroid hormone-mediated hypercalcemia
parathyroid receptor, raising serum calcium levels. Squamous and is diagnosed with simultaneously elevated serum
cell carcinomas, breast cancers, and renal cell carcinomas are calcium levels, with an inappropriately normal or ele
the tumors most commonly associated with hypercalcemia of vated intact parathyroid hormone level.
malignancy. In multiple myeloma, the hypercalcemia is caused • Parathyroidectomy is curative in approximately 90% of
by the release of factors that stimulate osteoclast activity. patients with primary hyperparathyroidism, but should
be performed by an experienced surgeon using mini
Other Causes mally invasive techniques.
Non-PTH-mediated hypercalcemia can be caused by sev
(Continued)
eral other mechanisms. Thyrotoxicosis can lead to mild
65
Calcium and Bone Disorders
CJI Hypoparathyroidism
I lypopar,1thyroidis111. commonly due lo trauma during neck
calcium levels should be measured at each follow-up visit. The
goal calcium levels should be low-normal without hypercal
surgcrv (t hyroidectomy or parat hyroidcctomy). is the most ciuria. The magnesium level should ideally be greater than
common cause or hypoc,1lcc111ia. l)uri11g hc,1d ,1rnl neck sur 2 mg/dL (0.83 mmol!L) and creatinine levels should remain in
gcrics. the p,m1thyroid glands can he in,1dvcrtc11tly removed or the normal range. If the urine calcium level is greater than
p,1 r..1 thyroid hormone production rn 11 he tra nsicntly decreased 300 mg/24 h (hypercalciuria), calcium and/or vitamin D replace
due to disruption orhlood supply. Only serial mcasLm:mcnts or ment needs to be decreased. Calcium is usually decreased first if
calciu111 levels wi 11 clctcrminc whether the damagc is t rn nsient. the vitamin D levels are within the normal sufficiency range.
I lypoparnthyroidism Glll also be caused by damage 1·ro111 racli KEY POINT
ation exposure. p,irathyrnid gland inl�1rctio11. inl'iltrative dis
• Ifhypoparathyroidism is the cause ofhypocalcemia, cor
c,1scs (hcrnochrornatosis. Wilson disease. grc1nulo111,1s). or
rection ofany coexisting hypomagnesemia to serum
autoimmune hypo1x1rathyroiclis111. Cl
magnesium 2 mg/dL (0.8 mmol!L) or higher is necessary.
Other Causes of Hypocalcemia
Other, less common causes of hypocalcemia include poor
calcium intake, activating mutations in the CASR gene, PTH Metabolic Bone Disease
resistance, increased phosphate binding in vascular space Osteopenia and Osteoporosis
(rhabdomyolysis or tumor lysis syndrome), increased citrate Physiology
chelation with large volume blood transfusions, sepsis, vita Bone mineral density begins to increase with puberty, and peak
min D deficiency, and hypomagnesemia. Low levels of mag bone mass is achieved in early adulthood. Sex hormones, estro
nesium (due to alcohol abuse or malnutrition) activate gen and testosterone, are crucial to increasing bone mineral
G-proteins that stimulate calcium-sensing receptors and density in women and men, respectively. Specifically, estrogen
decrease PTH secretion. has impact on osteoclast and osteoblast activity in both men and
66
Calcium and Bone Disorders
women. Towards the end of puberty, estrogen halts bone resorp Diagnosis
tion and signals the closure of epiphyseal plates. Bone mass The diagnosis of osteopenia is based on BMD testing.
begins to decline in women after menopause, with decreased Osteoporosis, however, can be diagnosed by BMD testing or
estrogen levels, and in men over age SO years. In men, the loss clinically in the patient with history of fragility fracture, hip
of testosterone typically accelerates bone loss after 70 years of fracture, or vertebral compression fracture.
age. Early cessation of sex hormone production in either sex, for DEXA assesses the density of the vertebral and hip bones
any reason, may accelerate the loss of bone mineral density. compared with healthy young-adult sex-matched reference
Bone loss occurs when the removal of old bone (osteoclastic values. The distal one-third of the radius can be used in
activity) exceeds the replacement with new bone (osteoblastic patients when the hip or vertebral BMD cannot be measured.
activity). Accelerated bone loss can often be attributed to hypo The score is based on the number of standard deviations above
gonadism or medications that promote bone loss. or below the mean reference value and is known as theT -score.
Those patients withT -scores at -1.0 and above have normal
Risk Assessment and Screening Guidelines bone density. AT -score between -1.0 and -2.S is defined as
Declining bone mineral density is associated with future frac low bone mass (osteopenia). Osteoporosis is defined as a
ture risk and therefore is an important component of fracture T -score below -2.S. Severe osteoporosis is defined as a T-score
risk assessment. Individual peak bone mass is determined by of -2.S or below with one or more fractures. In women and
genetic factors, nutrition, changes in hormone (estrogen, tes men younger than SO years, the International Society for
tosterone, thyroxine) levels, concomitant health conditions, Clinical Densitometry recommends that ethnic- or race
and physical activity level. adjusted Z-scores be used.The Z-score compares a patient's
The National Osteoporosis Foundation recommends that BMD with others of their same age and ethnicity, and osteopo
all postmenopausal women and men older than SO years of age rosis/osteopenia cannot be diagnosed in these patients. A
be evaluated for osteoporosis.This evaluation includes a thor Z-score of -2.0 or lower should be described as "low bone
ough history for potential risk factors and physical examination. mineral density for chronologic age" or "below the expected
This preliminary screening will determine if bone mineral den range for age." Patients with Z-scores above -2.0 are "within
sity (BMD) or vertebral imaging is necessary. Table 33 lists sev the expected range for age."
eral common risk factors for osteoporosis. If a patient is deemed In 2008, the World Health Organization (WHO) created
high risk, a study of BMD with DEXA may help further assess the Fracture Risk AssessmentTool (FRAX) calculator that fur
fracture risk.The DEXA is designed to measure BMD and estab ther defines the 10-year fracture risk for patients with osteope
lish risk of fracture in postmenopausal women. In young men nia, defined as aT-score between -1.0 to -2.S on DEXA.The
and premenopausal women, assessment of BMD for fracture FRAX score notes the probability of major osteoporotic fracture
risk is not advised or validated. Table 34 lists the U.S. Preventive and hip fracture in the next 10 years. If the risk of major osteo
ServicesTask Force recommendations for BMD testing. porotic fracture is greater than or equal to 20% or the risk of hip
67
Calcium a n d Bo n e Disorders
TABLE 34. U.S. Preventive Services Task Force hypercalciuria) is an appropriate set of laboratory tests to
Recommendations for Measurement of Bone Mineral screen for secondary causes ofBMD loss. These are modifiable
Density and Vertebral Imaging conditions that, if corrected, will result in increased BMD.
Bone Mineral Density Testing• These patients are typically young with either markedly low
BMD for age or a new fracture or patients of any age with mul
Women age 65 and older and men age 70 and older
tiple fractures.
Postmenopausal women and men age 50 to 69, based on risk With all secondary causes of decreased BMD, reversal of
factor profile
the cause should be the first line of therapy and subsequent
Those who have had a fracture, to determine degree of disease DEXA should be performed. If the BMD has not improved or
severity
the FRAX score suggests increased risk of fracture, treatment
Radiographic findings suggestive of osteoporosis or vertebral
deformity should be started. In the event of a fracture, the underlying
cause should still be addressed in addition to initiating phar
Glucocorticoid therapy for more than 3 months
macologic therapy for osteoporosis.
Primary hyperparathyroidism
Treatment for osteoporosis (to monitor therapeutic response) Pharmacologic Treatment Options
Vertebral lmagingb
Currently there are six categories of pharmacologic agents that
are FDA approved for the treatment of postmenopausal osteo
Women �70 and men �80 ifT-score at the spine, total hip, or porosis. These medications are bisphosphonates, calcitonin,
femoral neck is,;; -1.0
estrogens, estrogen agonists, parathyroid hormone, and the
Women aged 65-69 and men aged 75-79 ifT-score at the receptor activator of nuclear factor KB (RANK) ligand inhibitor
spine, total hip, or femoral neck is :51.5
family. Bisphosphonates are usually first-line therapy unless
In postmenopausal women age 50-64 and men aged 50-69 there is a compelling reason why another therapy should be
with the following risk factors:
used. The other modalities are typically used after a bisphos
Low-trauma fractures
phonate failure or inability to use the medication. Most of these
Historic height loss of 1.5 in or more (4 cm) medications can also be used for prevention of osteoporosis.
Height loss of 0.8 inches or more (2 cm) Prevention therapy may be used in patients with osteopenia
Recent or ongoing long-term glucocorticoid treatment who do not meet FRAX standards for therapy but have multiple
•BMD testing should be performed at DEXA facilities using accepted quality
risk factors such as high-risk medications (glucocorticoids or
assurance measures. antiestrogen, antiandrogen, or antiseizure medications) in
bVertebral imaging should be repeated when a new loss of height is noted or new combination with a strong family history of osteoporosis.
back pain is reported.
Bisphosphonates
fracture is greater than or equal to 3%, the patient's benefit Bisphosphonate medications work by inhibiting osteoclastic
from therapy exceeds the risk, and treatment should be offered. activity.Before starting any bisphosphonate therapy, vitamin D
The FRAX was validated for use in persons 40 to 90 years status and calcium levels should be evaluated, as bisphospho
of age who are not currently or previously treated with phar nates can lead to hypocalcemia. For oral bisphosphonates,
macotherapy for osteoporosis. The WHO has a web site that integrity of the esophageal lining and ability to swallow pills
offers an online FRAX calculator at www.shef.ac. uk/FRAX. are important. Kidney function should be assessed as bispho
In additional toBMD testing, vertebral imaging using radi sphonates are contraindicated in patients with an estimated
ographs is recommended in high-risk groups since many ver glomerular filtration rate less than 35 mL/min/1.73 m2 .
tebral fractures are asymptomatic. The presence of a vertebral Although rare, osteonecrosis of the jaw has been reported with
compression fracture establishes the clinical diagnosis of osteo bisphosphonate usage, particularly with high-dose intrave
porosis, regardless of T -score on DEXA, and treatment is rec nous administration and increased duration of the bisphos
ommended. Once a vertebral image is obtained, it only needs to phonate. Additionally, atypical femur fractures have been
be repeated if there is noted height loss or new back pain. reported with long-term usage. Regular questioning about
pain in the thigh or groin area is recommended for patients on
Evaluation of Secondary Causes of bisphosphonates. If patients report discomfort, a radiograph
Bone Mineral Density Loss should be obtained. To reduce the risk of these side effects, a
Most cases of osteoporosis are due to declining levels of sex drug holiday has been suggested in patients with low-risk
hormones which are non-modifiable, such as age, sex, meno osteoporosis (T-score greater than -2.S or single fractures) who
pause, height, and build. Some patients, however, have osteo have been on therapy for 3 to S years with stableBMD. During
porosis caused by secondary causes. Measurement of complete bisphosphonate therapy for prevention or treatment, men SO
blood count (for malignancy), complete metabolic panel (for to 70 years of age should consume 1000 mg/d of calcium and
calcium levels and kidney function), thyroid-stimulating hor women aged 51 years and older and men aged 71 years and
mone, 25-hydroxyvitamin D, and urine calcium (screening for older consume 1200 mg/d of calcium.
68
Calcium and Bone Disorders
Alendronate has been approved by the FDA for preven Parathyroid Hormone
tion and treatment of osteoporosis. The prevention dose is a Teriparatide (recombinant human PTH [1-34]) has been FDA
5-mg tablet daily or a 35-mg tablet weekly. The treatment dose approved for the treatment of osteoporosis in postmenopausal
is a 10-mg tablet daily or a 70-mg tablet weekly. Alendronate is women and men who are at high risk for fracture. "High risk"
also approved for treatment of men with osteoporosis as well is defined as patients with a T -score of -3.0 or less or patients
as treatment of both women and men with glucocorticoid who have either had a fracture or decreased BMD while on
induced osteoporosis. Alendronate has been shown to reduce bisphosphonate therapy. It is also approved for men and
the incidence of spine and hip fractures by approximately SO% women at high risk of fracture due to long-time glucocorticoid
over 3 years in patients with previous fractures. use. Teriparatide has bone-building properties in addition to
lbandronate is FDA approved for the treatment and pre the antiresorptive properties of the other agents. It is the only
vention of postmenopausal osteoporosis. The dosage is a bone-building treatment option for osteoporosis.
150-mg tablet monthly or 3 mg every 3 months by intravenous Teriparatide is an anabolic steroid that is administered by
injection. There is FDA approval for the oral formulation for a 20-µg daily subcutaneous injection; it is approved for up to
osteoporosis prevention only. lbandronate primarily reduces 24 months over a patient's lifetime. After the 24-month dura
risk of vertebral fractures by 50% in 3 years. tion, an antiresorptive agent (such as bisphosphonates or den
Risedronate is FDA approved for the prevention and treat osumab) can be administered to maintain BMD gains achieved
ment of osteoporosis. The treatment dose is a 5-mg tablet daily, with teriparatide.
a 35-mg tablet weekly, a 75-mg tablet on two consecutive days
every month, or a 150-mg tablet monthly. Risedronate is also Receptor Activator of Nuclear Factor KB (RANK)
approved for treatment of osteoporosis in men and women Ligand Inhibitors
with glucocorticoid-induced osteoporosis. Risedronate Denosumab is a receptor activator of nuclear factor KB (RANK)
reduces the incidence of vertebral fracture by approximately ligand inhibitors that is FDA approved for the treatment of
45% and nonvertebral fractures by one-third over 3 years. osteoporosis in postmenopausal women who are at high risk
Zoledronic acid has been FDA approved for the preven of fracture. It is an antiresorptive agent, like the bisphospho
tion and treatment of postmenopausal osteoporosis in women, nates with much the same effect and outcomes. It is also
for improvement of bone mass in men with osteoporosis, and approved for treatment of osteoporosis in men and those
for the prevention and treatment of glucocorticoid-induced undergoing treatment of certain cancers, such as prostate can
osteoporosis in men and women. Recently zoledronic acid has cer, who are at high risk for fractures. Denosumab is given by
been approved for secondary prevention of fractures in subcutaneous injection (60 mg every 6 months).
patients who have had recent low-trauma hip fracture. The
treatment dose of zoledronic acid is 5 mg intravenously annu Annual Reassessment of Patients with Low Bone Mass
ally or once every 2 years for prevention. Once an initial DEXA scan has been obtained, every effort
should be made to have subsequent scans done on the same
Calcitonin machine. Once a repeat scan has been done, change in BMD,
Calcitonin is FDA approved for the treatment of osteoporosis not T -score, from year to year is the appropriate way to inter
in women who are Sor more years postmenopausal. Calcitonin pret whether there has been a significant change in BMD. Most
(200 U) is delivered in a single daily intranasal spray. reports will not show a statistically significant change in the
Subcutaneous administration is also available but is used less BMD from the previous test. If not noted on the report, a cal
f requently. Calcitonin should be used with caution with culated change of about 4% likely represents a statistically
patients who have an allergy to salmon, allergic rhinitis, or significant change. Annually, a complete clinical evaluation of
epistaxis. Very rarely, patients can also have an anaphylactic the patient, determination of risk factors for bone loss, and
response that requires emergency attention and discontinua evaluation for development of secondary causes of bone loss
tion of the medication. should be performed, starting with a history and physical
examination.
Estrogen Agonists and Antagonists
The use of estrogen to maintain bone health in postmenopau Vitamin D Deficiency
sal women has fallen out of favor because of data indicating In promoting absorption from the gut, vitamin D enables proper
that estrogen increases the risk of cardiovascular disease and bone mineralization by maintenance of calcium and phospho
breast cancer. Therefore, estrogen use for osteoporosis preven rus levels. Vitamin D also modulates the actions of osteoblasts
tion should be limited to younger women with premature and osteoclasts to ensure proper bone growth and remodeling.
ovarian failure and postmenopausal women who also require Chronically low levels of vitamin D can lead to rickets in chil
its beneficial effects for hot flushes or vaginal dryness. dren and osteomalacia in adults (see MKSAP 17 Nephrology).
Raloxifine has been approved for the treatment of post In addition to bone health, vitamin D plays a role in
menopausal osteoporosis. The treatment dose is a 60-mg tab inflammation reduction, growth regulation of various cell
let to be taken with or without food. types, immune function, and neuromuscular signaling.
69
Calcium and Bone Disorders
In assessing serum levels of vitamin D, concentrations of Vitamin D toxicity is a very rare entity but one to be aware
25-hydroxyvitamin D are the best indicator of vitamin D sta of. The effects of vitamin D levels greater than 90 ng/mL (225
tus. It reflects vitamin D produced cutaneously and that nmol/L) include hypercalcemia. As a fat-soluble vitamin,
obtained from food and supplements and has a circulating decreasing vitamin D levels that are once elevated can be a
half-life of 15 days. slow process requiring continued monitoring.
There are three levels of vitamin D status: sufficient
KEY POINTS
(25-hydroxyvitamin D 2':30 ng/mL [75 nmol/L]), insufficient
(25-hydroxyvitamin D 21-29 ng/mL [52.4-72.4 nmol/L]), and • The U.S. Preventive Services Task Force recommends
deficient (25-hydroxyvitamin D ::::20 ng/mL [50 nmol!L]). screening for osteoporosis in women aged 65 years and
Because vitamin D levels can be affected by sun exposure, fall older and in younger women whose fracture risk is
through winter months are ideal times to measure vitamin D equal to or greater than that of a 65-year old white
levels. It is best to measure vitamin D levels at the same time women who has no additional risk factors.
each year unless treatment is being followed. In general, the • The presence of a vertebral compression fracture makes
optimal levels of vitamin D are those that prevent PTH levels the clinical diagnosis of osteoporosis, regardless of
from increasing to above normal levels. Increased PTH levels T-score on dual-energy x-ray absorptiometry (DEXA)
will lead to increased calcium withdrawal from the bones. In scan, and treatment is recommended.
an attempt to find the optimal vitamin D level, several studies • Fracture Risk Assessment Tool (FRAX) score can help
have looked at vitamin D levels related to cancer incidence, identify which patients are most likely to benefit from
muscle stability and falls, immune status, and mood, in addi osteoporosis treatment; bisphosphonate therapy is first
tion to bone health. Among most experts, a level between 30 line therapy for postmenopausal osteoporosis treatment
and 40 ng/mL (75-100 nmol/L) is deemed sufficient for pre and prevention.
ventive health. Based on these levels, about 30% to 60% of
• A 25-hydroxyvitamin D level between 30 and 40 ng/mL HVC
Americans have low vitamin D levels, therefore most expert
(75-100 nmo!/L} is deemed sufficient for bone health;
groups recommend screening all patients at least once. Those most expert groups recommend screening all groups at
with darker skin, decreased sun exposure, or increased
least once for evidence of deficiency since U.S. inci-
demands (pregnancy) often have low levels. dence is 30% to 60% of the population, however, it
Special populations will have lower levels of vitamin D
should not be a serial, recurring screening test.
owing to medical conditions or medication side effects. In addi
tion, obesity has been correlated with lower vitamin D levels
possibly related to fat sequestration. Certain antiseizure medica Paget Disease of Bone
tions (phenobarbital and phenytoin) may increase the metabo Paget disease of bone is characterized by rapid and chaotic
lism of vitamin D to inactive forms. Glucocorticoids can decrease bone remodeling leading to disorganized bone microarchitec
vitamin D metabolism. Agents that decrease absorption such as ture. This disease more commonly affects persons ofEuropean
orlistat and cholesterol lowering agents can decrease vitamin D descent during the sixth decade, with a prevalence of 3% to
absorption. Similarly, patients with malabsorption disorders, 10% in the elderly. Paramyxovirus infection of osteoclastic
including those with celiac disease and those who had bariatric precursors is thought to be one possible cause, although about
surgery, can have decreased levels of vitamin D. In these special 15% of people with Paget disease have a family member with
patient populations, not only does screening for deficiency need the disease. Paget disease appears to be inherited in an autoso
to be more frequent, but repletion may be more challenging. It is mal dominant manner with incomplete penetrance.
recommended that these populations be given at least two to
three times more vitamin D to maintain adequate levels. Clinical Presentation
The most common clinical manifestation is asymptomatic
Recommendations elevated serum alkaline phosphatase levels; only 30% of
The current National Osteoporosis Foundation andEndocrine patients have symptoms at diagnosis. In some patients, the
Society recommendation for adults 19 to 70 years of age is at dysfunctional bone structure creates expansion in the bone
least 600 U/d of vitamin D to maximize bone health, however, leading to pain, swelling, and warmth. Bones of the axial skel
to raise blood levels consistently above 30 ng/dL (75 nmol/L} eton are most frequently affected, namely the pelvis (70%),
may require 1500 to 2000 U/d. In adults older than 70 years of femur (55%), lumbar spine (53%), skull (42%), and tibia (30%).
age, 800 U of supplemental vitamin D per day is recom As a result, patients tend to have headache, sensorineural
mended to maximize bone health; however, 1500 to 2000 U/d hearing loss, and bowing of the long bones (Figure 16). The
may be required to keep levels consistently above 30 ng/dL abnormal bone growth may also lead to nerve impingement
(75 nmol/L). In treating the deficient patient, 50,000 U of causing pain or neurologic deficits. Rarely, patients can
either ergocalciferol or cholecalciferol is recommended, once develop increased vascular shunting to bones with resultant
weekly for 8 weeks. Once sufficiency is attained, maintenance right-sided heart failure, cellular transformation to osteosar
therapy of 1500 to 2000 U/d is recommended. coma, and hypercalcemia of immobilization.
70
Bibliography
Bibliography
Disorders of Glucose Metabolism
Bergenstal RM, Klonoff DC, Garg SK, et al; ASPIRE In-HOME Study Group.
Threshold-based insulin-pump interruption for reduction of hypoglyce
mia. N Engl J Med. 2013 Jul 18;369(3):224-32. [PMID: 23789889]
Bergenstal RM, Tamborlane WV, Ahmann A, et al; STAR 3 STUDY Group.
Effectiveness of sensor-augmented insulin-pump therapy in type l diabe
tes. N Engl J Med. 2010 Jul 22;363(4):311-20. [PMID: 20587585]
Committee on Practice Bulletins-Obstetrics. Practice Bulletin No. 137:
Gestational diabetes mellitus_ Obstet Gynecol. 2013 Aug;l22(2 Pt 1):406-16.
[PMID: 23969827]
FIGURE 16. Radiograph showing Paget disease of bone in the left lateral Cowie CC, Rust KF. Byrd-Holt DD, et al. Prevalence of diabetes and high risk
tibia of a 71-year-old woman. Note the anterior bone, cortical thickening, and for diabetes using A\c criteria in the U.S. population in 1988-2006. Diabetes
bone enlargement as compared with the normal radiograph on the right. The Care. 2010 Mar;33(3J:562-8. [PMID: 20067953]
long-standing Paget disease resulted in a left leg that was 2.5 cm (1 in) shorter Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult
than the right. hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline.
J Endocrinol Metab. 2009 Mar;94(3):709-28. [PMID: 19088155]
Gregg EW. Chen H, Wagenknecht LE. et al. Association of an intensive lifestyle
intervention with remission of type 2 diabetes. JAMA. 2012 Dec
19;308(23):2489-96. [PMID: 23288372]
Diagnosis Malanda UL, Welschen LM, Riphagen II, et al. Self-monitoring of blood glu
The diagnosis of Paget disease should be suspected in asymp cose in patients with type 2 diabetes mellitus who are not using insulin.
Cochrane Database Syst Rev. 2012 Jan 18;1:CD005060. [PMID: 22258959]
tomatic patients with an isolated elevation of alkaline phos
Nathan DM; DCCT/EDIC Research Group. The Diabetes Control and
phatase without evidence of liver disease. In these patients Complications Trial/Epidemiology of Diabetes Interventions and
the most sensitive test is a nuclear bone scan which will Complications Study at 30 years: Overview. Diabetes Care. 2014Jan;37(1):9-
16. [PMID: 24356592]
detect areas of increased metabolic activity. Plain films of Qaseem A. Humphrey LL. Sweet DE, et al. Oral pharmacologic treatment of type
these areas should be obtained to identify pathognomonic 2 diabetes mellitus: a clinical practice guideline from the American College
of Physicians. Ann Intern Med. 2012 Feb 7;156(3):218-31. [PMID: 22312141]
pagetic lesions such as focal osteolysis with coarsening of the
Yeh HC, Brown TT, Maruthur N, et al. Comparative effectiveness and safety of
trabecular pattern and cortical thickening. In symptomatic methods on insulin delivery and glucose monitoring for diabetes mellitus.
patients with bone pain, plain films of painful areas may be Ann Intern Med. 2012 Sep 4;157(5):336-47. [PMID: 22777524]
the initial imaging test, although many experts recommend a Disorders of the Pituitary Gland
baseline bone scan once the diagnosis is confirmed prior to Colao A, Bronstein MD, Freda P, et al. Pasireotide versus octreotide in acro
megaly: A head-to-head superiority study. J Clin Endocrinol Metab. 2014
initiating treatment. Mar:99(3):791-9. [PMID: 24423324]
Colao A, Petersenn S. Newell-Price J, et al. A 12-month phase 3 study of
Treatment pasireotide in Cushing's disease. N Engl J Med. 2012 Mar 8;366(10):914-24.
[PMID: 22397653]
The main therapies for Paget disease of bone are the nitrogen
Freda PU, Beckers AM, Katznelson L. et al. Pituitary incidentaloma: an endo
containing bisphosphonate medications (alendronate, crine society clinical practice guideline. J Clin Endocrinol Metab. 2011
pamidronate, risedronate, and zoledronic acid). The main Apr:96(4):894-904. [PMID: 21474686]
indications for antiresorptive therapy are (1) pain caused by Katznelson L, Laws ER Jr, Melmed S, et al. Acromegaly: an endocrine society
clinical practice guideline. J Clin Endocrinol Metab. 2014 Nov;99(11):3933-
the increased metabolic activity; (2) planned surgery at site of 51. [PMID: 25356808]
pagetic bone disease, and (3) hypercalcemia due to multiple Klibanski A. Clinical Practice. Prolactinomas. N Engl J Med. 2010 Apr
l:362(13):1219-26. [PMID: 20357284]
affected sites. There is no evidence that antiresorptive therapy
Korbonits M, Storr H, Kumar! AV. Familial pituitary adenomas-who should be
is beneficial in asymptomatic patients. These medications are tested for AIP mutations? Clin Endocrinol (OxO. 2012 Sep;77(3):351-6.
ideal because they suppress the rapid bone turnover that is [PMID: 22612670]
characteristic of Paget disease. Decreases in alkaline phos Malchiodi E. Profka E, Ferrante E. et al. Thyrotropin-secreting pituitary adeno
mas, Outcome of pituitary surgery and irradiation. J Clin Endocrinol Metab.
phatase can be noted within 10 to 14 days after the initiation of 2014 Jun:99(6):2069-76. [PMID: 24552222]
therapy with a nadir reached in 3 to 6 months. NSA!Ds and Melmed S, Casanueva FF, Hoffman AR. et al. Diagnosis and treatment of
antineuropathic medications can also be used for pain control hyperprolactinemia: An Endocrine Society clinical practice guideline.
J Clin Endocrinol Metab. 2011 Feb;96(2):273-88. [PMID: 21296991]
in these patients. For patients with pseudofractures, orthope Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing's syn
dic stabilization may be required. drome: an Endocrine Society clinical practice guideline. J Clin Endocrinol
Metab. 2008 May;93(5):1526-40. [PMID: 18334580]
KEY POINTS Rajasekaran S. Vanderpump M, Baldeweq S, et al. UK guidelines for the man
agement of pituitary apoplexy. Clin Endocrinol (OxO. 2011 Jan;74(1):9-20.
• The most common clinical manifestation of Paget dis [PMID: 21044119]
ease of bone is asymptomatic elevated alkaline phos Vasilev V, Daily AF, Petrossians P, et al. Familial pituitary tumor syndromes_
phate levels. Endocrine Practice. 2011 Jul-Aug:17 Suppl 3:41-6. [PMID: 21613050]
• The main therapy for Paget disease of bone is the Disorders of the Adrenal Glands
Cordera F. Grant C. van Heerden J, et al. Androgen-secreting adrenal tumors.
nitrogen-containing bisphosphonate medications Surgery. 2003 Dec;l34(6):874-80. [PMID: 14668717]
(alendronate, pamidronate, risedronate, and zole Eisenhofer G, Goldstein D, Walther M, et al_ Biochemical diagnosis of pheo
dronic acid). chromocytoma: How to distinguish true- from false-positive test results. J
Clin Endocrinol Metab. 2003 Jun;88(6):2656-66. [PMID: 12788870]
71
Bibliography
Fishbein L, Orlowski R, Cohen D. Pheochromocytoma/Paraganglioma: Review Barbieri RL, Makris A. Randall RW, Daniels G. Kistner RW, Ryan KJ. Insulin
of perioperative management of blood pressure and update on genetic stimulates androgen accumulation in incubations of ovarian stroma
mutations associated with pheochromocytoma. J Clin Hypertens obtained from women with hyperandrogenism. J Clin Endocrinol Metab.
(Greenwich). 2013 Jun;l5(6):428-34. [PMID: 23730992] 1986 May:62(5):904-10. [PMIO: 3514651]
Funder JW, Carey RM, Fardella C. et al. Case detection, diagnosis, and treat Belvisi L, Bornbelli F, Sironi L. Doldi N. Organ-specific autoimmunity in
ment of patients with primary aldosteronism: an endocrine society clinical patients with premature ovarian failure. J Endocrinol Invest. 1993
practice guideline. J Clin Endocrinol Metab. 2008 Sep;93(9):3266-81. Dec;l6(11):889-92. [PMID: 8144865]
[PMID: 18552288] de Moraes Ruehsen M, Blizzard RM. Garcia-Bunuel R, Jones GS. Autoimmunity
Lenders J W, Duh QY, Eisenhofer G. et al. Pheochromocytoma and paragan and ovarian failure. Am J Obstet Gynecol. 1972 Mar:112(5):693-703. [PMID:
glioma: An endocrine society clinical practice guideline. J Clin Endocrinol 4551032]
Metab. 2014 Jun:99:1915-1942. [PMID: 24893135] Ferrnindez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse
Morelli V, Reimondo G. Giordano R. et al. Long-term follow-up in adrenal effects of testosterone therapy in adult men: a systematic review and rneta
incidentalomas: an Italian multicenter study. J Clin Endocrinol Metab. 2014 analysis. J Clio Endocrinol Metab. 2010 Jun:95(6):2560-75. [PMID: 20525906]
Mar:99(3):827-34. [PMID: 24423350] Hoek A, Schoemaker J. Drexhage HA. Premature ovarian failure and ovarian
Neary N. Nieman L. Adrenal insufficiency: etiology, diagnosis and treatment. Curr autoimmunity. Endocr Rev. 1997 Feb;l8(1):107-34. [PMID: 9034788]
Opin Endocrinol Diabetes Obesity. 2010 Jun:17(3):217-23. [PMID: 20375886] Kauffman RP, CastracaneVD. Premature ovarian failure associated with auto
Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: immune polyglandular syndrome: pathophysiological mechanisms and
an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. future fertility. J Womens Health (Larchrnt). 2003 Jun:12(5):513-20. [PMID:
2008 May;93(5):1526-40. [PMID: 18334580] 12869299]
Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with Kong MF, Jeffcoate W. Eighty-six cases of Addison's disease. Clio Endocrinol
septic shock. N Engl J Med. 2008 Jan 10;358(2):lll-24. [PMID: 18184957] (OxO. 1994 Dec;41(6):757-61. [PMID: 7889611]
Young WF, Jr. Clinical practice. The incidentally discovered adrenal mass. N Legro RS, Barnhart HX. Schlaff WO, et al; Cooperative Multicenter
Engl J Med. 2007 Feb 8;356(6):601-10. [PMID: 17287480] Reproductive Medicine Network. Clomiphene, metforrnin, or both for
Zeiger MA, Thompson GB, Duh QY, et al. The American Association of Clinical infertility in the polycystic ovary syndrome. N Engl J Med. 2007 Feb
Endocrinologists and American Association of Endocrine Surgeons medi 8;356(6):551-66. [PMID: 17287476]
cal guidelines for the management of adrenal incidentalomas. Endocr Mignot MH, Schoemaker J. Kleingeld M, Rao BR, Drexhage HA. Premature
Pract. 2009 Jul-Aug;l5 Suppl 1:1-20. [PMID: 19632967] ovarian failure. I: The association with autoimmunity. Eur J Obstet Gynecol
Reprod Biol. 1989 Jan;30(1) :59-66. [PMID: 2647538]
Disorders of the Thyroid Gland
Moncayo-Naveda H, Moncayo R. Benz R, Wolf A, Lauritzen C. Organ-specific
American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and antibodies against ovary in patients with systemic lupus erythematosus.
Differentiated Thyroid Cancer. Cooper OS, Doherty GM, Haugen BR, et al. Am J Obstet Gynecol. 1989 May;l60(5 Pt 1):1227-9. [PMID: 2729399]
Revised American Thyroid Association management guidelines for patients
with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009 Plymale SR. Matej LA, Jones RE, Friedl KE. Inhibition of sex hom1one-binding
Nov;l9(ll):ll67-214. Erratum in: Thyroid. 2010Aug;20(8):942. [PMID: 19860577] globulin production in the human hepatoma (Hep G2) cell line by insulin and
prolactin. J Clin Endocrinol Metab. 1988 Sep;67(3):460-4. [PMID: 2842359]
Bartalena L. Diagnosis and management of Graves disease: a global overview.
Nat Rev Endocrinol. 2013 Dec;9(12):724-34. [PMID: 24126481] Ryan MM, Jones HR Jr. Myasthenia gravis and premature ovarian failure.
Muscle Nerve. 2004 Aug;30(2):231-3. [PMID: 15266640]
Biondi B. Natural history, diagnosis and management of subclinical thyroid
dysfunction. Best Pract Res Clio Endocrinol Metab. 2012 Aug;26(4):431-46. Vigen R, O'Donnell CI, Baron AE. et al. Association of testosterone therapy
[PMID: 22863386] with mortality, myocardial infarction, and stroke in men with low testos
terone levels. JAMA. 2013 Nov 6;310(17):1829-36. Erratum in: JAMA. 2014
Bogazzi F, Bartalena L, Martino E. Approach to the patient with amiodarone Mar 5;311(9):967. [PMID: 24193080]
induced thyrotoxicosis. J Clin Endocrinol Metab. 2010 Jun;95(6):2529-35.
[PMID: 20525904] Calcium and Bone Disorders
Cooper OS, Biondi B. Subclinical thyroid disease. Lancet. 2012 Mar Al-Azem H, Khan AA. Hypoparathyroidism. Best Pract Res Clin Endocrinol
24;379(9821):1142-54. [PMID: 22273398] Metab 2012 Aug:26(4):517-22. [PMID: 22863393]
Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory Bischoff-Ferrari H A. Willert WC. Orav E J, et al. A pooled analysis of vitamin
support for the diagnosis and monitoring of thyroid disease. Clin D dose requirements for fracture prevention. N Engl J Med. 2012 Jul
Endocrinol (OxO. 2003 Feb:58(2):138-40. [PMID: 12580927] 5;367(1):40-9. [PMID: 22762317]
Devdhar M, Ousman YH, Burman KO. Hypothyroidism. Endocrinol Metab Halick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81.
Clin North Am. 2007 Sep:36(3):595-615, v. [PMID: 17673121] [PMID: 17634462]
Farwell AP. Nonthyroidal illness syndrome. Curr Opin Endocrinol Diabetes Halick MF, Binkley N, Bischoff-Ferrari HA, et al. Evaluation. treatment and
Obes. 2013 Oct:20(5):478-84. [PMID: 23974778] prevention of vitamin D deficiency: an Endocrine Society clinical practice
Klubo-Gwiezdzinska J, Wartofsky L. Thyroid emergencies. Med Clin North guideline. J Clio Endocrinol Metab. 2011 Jul:96(7):1911-30. [PMID: 21646368]
Am. 2012 Mar:96(2):385-403. [PMID: 22443982] Marcocci C, Cetani F. Primary hyperparathyroidism. N Engl J Med. 2011 Dec
Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med. 2003 Jun 22;365(25):2389-97. [PMID: 22187986]
26;348(26):2646-55. Review. Erratum in: N Engl J Med. 2003 Aug Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D.
7:349(6):620. [PMID: 12826640] Washington, DC: National Academy Press, 2010.
Siegel RD, Lee SL Toxic nodular goiter. Toxic adenoma and toxic multinodular National Osteoporosis Foundation. Clinician's Guide to Prevention and
goiter. Endocrinol Metab Clin North Arn.1998 Mar:27(1):151-68. [PMID: 9534034] Treatment of Osteoporosis. Washington, DC: National Osteoporosis
Stagnaro-Green A, Abalovich M, Alexander E. et al; American Thyroid Foundation, 2014.
Association Taskforce on Thyroid Disease During Pregnancy and Ralston SH. Pager's disease of the bone. N Engl J Med. 2013 Feb 14:368(7):644-
Postpartum. Guidelines of the American Thyroid Association for the diag 50. [PMID: 23406029]
nosis and management of thyroid disease during pregnancy and postpar Sharma OP. Hypercalcemia in granulomatous disorders: a clinical review. Curr
tum. Thyroid. 2011 Oct:21(10):1081-125. [PMID: 21787128] Opin Pulm Med. 2000 Sep:6(5):442-7. [PMID: 10958237]
Reproductive Disorders Shoback D. Hypoparathyroidism. N Engl J Med. 2008 Jul 24:359(4):391-403.
Bakalov VK,VanderhoofVH, Bondy CA. Nelson LM. Adrenal antibodies detect [PMID: 18650515]
asymptomatic auto-immune adrenal insufficiency in young women with Wolpowitz D, Gilchrest BA. The vitamin D questions: how much do you need
spontaneous premature ovarian failure. Hum Reprod. 2002 Aug;l7(8):2096- and how should you get it? J Arn Acad Dermatol. 2006 Feb:54(2):301-17.
100. [PMID: 12151443] [PMID: 16443061]
72
Endocrinology and Metabolism
Self-Assessment Test
This self-assessment test contains one-best-answer multiple-choice questions. Please read these directions carefully
before answering the questions. Answers, critiques, and bibliographies immediately follow these multiple-choice
questions. The American College of Physicians is accredited by the Accreditation Council for Continuing Medical
Education (ACCME) to provide continuing medical education for physicians.
The American College of Physicians designates MKSAP 17 Endocrinology and Metabolism for a maximum of14 AMA
PRA Category 1 CreditsTM _ Physicians should claim only the credit commensurate with the extent of their partici
pation in the activity.
If you do not have a IO-digit order number and 8-digit ACP ID number or if you need help creating a username and
password to access the MKSAP 17 online answer sheets, go to mksap.acponline.org or email custserv@acponline.org.
CME credit is available from the publication date of December 31, 2015, until December 31, 2018. You may submit
your answer sheets at any time during this period.
73
Directions
Each of the numbered items is followed by lettered answers. Select the ONE lettered answer that is BEST in each case.
Item 1 Item 3
A 23-year-old woman is evaluated because of a 1-week his A 31-year-old woman is evaluated following her recent
tory of palpitations. She also reports some heat intolerance discovery that she is pregnant at approximately 10 weeks'
and mild anxiety during the last several weeks, but she oth gestation. Medical history is significant for a prolactinoma
erwise feels well. She is in the first trimester of an otherwise diagnosed 2 years ago during an evaluation for amenor
uncomplicated first pregnancy. Her only medication is a rhea. At the time of diagnosis, her serum prolactin level
prenatal vitamin. was 184 ng/mL (184 µg/L), and a 1.4-cm pituitary adenoma
On physical examination, she is afebrile, blood pres extending above the sella was detected on MRI without
sure is 110/72 mm Hg, pulse rate is 105/min, and respi evidence of mass effect. She was treated with bromocrip
ration rate is 13/min. BM! is 20. The skin is warm and tine with return of regular menses. She discontinued the
moist. There is no proptosis or lid lag. Examination of the bromocriptine when she found that she was pregnant. She
neck shows a diffusely enlarged thyroid with an audible is currently without symptoms. She does not have new
bruit over both lobes. Cardiopulmonary and abdominal or severe headache. Medical history is otherwise unre
examinations are unremarkable. Neurologic examina markable, and her only current medication is a prenatal
tion reveals a fine resting tremor of the hands and brisk multivitamin.
reflexes. On physical examination, vital signs are normal. Visual
Laboratory studies: fields are full to confrontation, and the remainder of her
Thyroid-stimulating hormone <0.008 µU/mL examination is normal.
(0.008 mU/L) Which of the following is the most appropriate next step in
Free thyroxine (T4 ) 5.5 ng/dL (70.9 pmol/L) management?
Total triiodothyronine (T} 400 ng/dL (6.2 nmol/L)
Thyroid-stimulating 4.5 (normal <1.3) (A) Check serum prolactin level
immunoglobulin index (B) Formal visual field testing
(C) Repeat pituitary MRI
Which of the following is the most appropriate treatment? (D) Restart bromocriptine
(A) Methimazole
(B) Propylthiouracil Item 4
(C) Radioactive iodine A 48-year-old woman returns for a follow-up visit for man
(D) Thyroidectomy agement of type 1 diabetes mellitus. She reports doing well
since the last visit. Overall, she believes that most of her
blood glucose levels are at goal, but is concerned about occa
Item 2 sional episodes of hyperglycemia occurring in the morning
A 34-year-old man is evaluated for episodic palpitations of before breakfast. She eats a bedtime snack every night that
8 months' duration. The palpitations last 5 to 10 minutes is not covered with mealtime insulin. Review of her blood
and then resolve spontaneously. They are usually associated glucose log demonstrates morning fasting blood glucose
with sweating and anxiety. Medical history is significant for values from 80 to 190 mg/dL (4.4-10.5 mmol/L). Her other
thyroidectomy for medullary thyroid carcinoma diagnosed premeal and bedtime values range from 100 to 120 mg/dL
at 12 years of age. His father has also undergone thyroidec (5.5-6.7 mmol/L). She exercises two to three times per week
tomy for medullary thyroid cancer. His only medication is in the evening. Medical history is significant for hyperten
levothyroxine. sion and hyperlipidemia.
On physical examination, blood pressure is 164/ Medications are insulin glargine, insulin lispro, rami
92 mm Hg, pulse rate is 106/min, and respiration rate is 12/ pril, simvastatin, and aspirin.
min. Auscultation of the heart reveals a regular tachycardia On physical examination, blood pressure is 130/72
without murmurs. The remainder of his examination is mm Hg and pulse rate is 67/min. BM! is 24. The remainder
unremarkable. of the examination is unremarkable.
Laboratory studies show a 24-hour urine excretion of Results of laboratory studies show a hemoglobin
catecholamines of 310 µg/m2/24 h (1832.1 nmol/m2/24 h) A 1 c level of 6.9% and serum creatinine level of 1.0 mg/dL
and metanephrines of 3400 µg/24 h (17,238 nmol/24 h). (88.4 µmol/L). Serum electrolytes are normal.
In addition to the presenting diag nosis, which of Which of the following is the most appropriate manage
the follow ing disorders is this patient most likely to ment of this patient's occasional fasting hyperglycemia?
develop? (A) Add insulin lispro at bedtime
(A) lnsulinoma (B) Add metformin
(B) Neurofibroma (C) Increase insulin glargine dose
(C) Primary hyperparathyroidism (D) Measure 3 AM blood glucose level
(D) Prolactinoma (E) Continue current regimen
75
Self-Assessment Test
76
Self-Assessment Test
Item 9 twice. Her last menstrual period was 4 months ago. She
An 18-year-old woman is evaluated for primary amenor also notes low libido and dyspareunia. She has not had
rhea. Her cognitive function is normal, and she is not sex weight changes, constipation, hair loss or hirsutism, or
ually active. Her personal and family medical history is skin changes.
unremarkable. She takes no medications. Her medical history is significant for primary hypothy
On physical examination, temperature is 36.1 °C (97.0 °F), roidism and bipolar disorder. Medications are levothyrox
blood pressure is 110/70 mm Hg, pulse rate is 72/min, and ine, lithium, and risperidone. She reports that she has been
respiration rate is 16/min; BM! is 20. Her height is 147 cm stable on these medications for a few years and feels well.
(58 in). Physical examination and secondary sex character She plans to discuss her medications with her psychiatrist
istics are normal, with Tanner stage IV breast and pubic hair prior to pregnancy.
development. On physical examination, blood pressure is 118/72 mm
Pregnancy testing is negative. On subsequent lab Hg and pulse rate is 82/min. BM! is 24. The thyroid is normal.
oratory studies estradiol level was undetectable, serum Visual fields are intact.
follicle-stimulating hormone level is 72 mU/mL (72 Laboratory studies:
U/L}, and serum luteinizing hormone level is 46 mU/mL Follicle-stimulating hormone 1.3 mU/mL (1.3 U/L}
(46 U/L}. Luteinizing hormone 2.0 mU/mL (2.0 U!L)
Prolactin 102 ng/mL (102 µg/L}
Which of the following is the most appropriate manage Thyroid-stimulating hormone 1.1 µU/mL (1.1 mU/L}
ment?
(A) Initiate estrogen and progestin therapy Which of the following is the most likely cause of her
(B) Measure serum prolactin hyperprolactinemia?
(C) Measure thyroid-stimulating hormone (A) Hypothyroidism
(D) Perform pituitary MRI (B) Lithium
(C) Pituitary adenoma
Item 10 (D) Risperidone
A 32-year-old man is evaluated for a 1-week history of
severe neck pain. He also has heat intolerance, palpitations, Item 12
and insomnia. Medical history is significant only for a viral A 55-year-old woman is evaluated for a new-patient
upper respiratory tract infection 3 weeks ago. He takes no visit. Medical history is significant for an eating disorder.
medications. Although she has maintained a normal weight for the past
On physical examination, he appears anxious and is 20 years, she notes that prior to that time her weight would
sweating. There is no proptosis or lid lag. Examination of fluctuate in a range correlating with BM!s of 17 to 19. She
the thyroid reveals a normal-sized gland that is very tender has otherwise been healthy and currently feels well. She
to palpation. There are no thyroid nodules. The heart rate is is postmenopausal and a never-smoker. Family history is
regular but tachycardic. The lungs are clear. significant for postmenopausal osteoporosis in her mother.
Laboratory studies: Her medications are over-the-counter calcium and vitamin
Thyroid-stimulating <0.008 µU/mL (0.008 mU/L} D supplements.
hormone On physical examination, temperature is 36.3 °c (97.3 °F},
Free thyroxine (T.) 3.2 ng/dL (41.3 pmol/L blood pressure is 137/81 mm Hg, pulse rate is 76/min, and
Total triiodothyronine (T) 310 ng/dL (4.8 nmol/L} respiration rate is 11/min. BM! is 21. She has mild thoracic
Thyroid-stimulating <1.3 (normal, <1.3) kyphosis but no skeletal tenderness. The remainder of the
immunoglobulin index examination is unremarkable.
24-Hour radioactive iodine 5% (low) Results of laboratory studies are significant for a serum
uptake calcium level of 9.1 mg/dL (2.3 mmol/L} and 25-hydroxyvi
tamin D level of 40 ng/mL (99.8 nmol/L}; thyroid function
Which of the following is the most appropriate treatment? studies are normal.
Dual-energy x-ray absorptiometry (DEXA) scan shows
(A) Methimazole T-scores of -1.8 in the femoral neck and -1.9 in the lumbar
(B) Metoprolol spine. Ten-year fracture risk using the Fracture Risk Assess
(C) Propylthiouracil ment Tool (FRAX) is 6.9% for major osteoporotic fracture
(D} Radioactive iodine and 0.7% for hip fracture. Plain radiographs of the spine
show no evidence of compression fracture.
Which of the following is the most appropriate manage
Item 11 ment of this patient?
A 30-year-old woman is evaluated for amenorrhea. She (A) Begin raloxifene
and her husband are interested in pregnancy in the
next year, and they are concerned that they will not be (B) Repeat DEXA scan in 2 years
able to conceive. Her menses became irregular about (C) Replace calcium with cholecalciferol
2 years ago. In the past 12 months, she has had menses (D) Start bisphosphonate therapy
77
Self-Assessment Test
Item 15 Item 17
A 55-year-old woman is seen in follow-up for low bone A 74-year-old woman is evaluated for a diagnosis of primary
mass and vitamin D deficiency. Cortical bone thinning was hyperparathyroidism made after an elevated serum calcium
noted on radiographs of her right ankle following a fall 3 level was incidentally discovered on laboratory studies. She
months ago. Subsequent evaluation included a dual-energy has no symptoms associated with hypercalcemia. Medical
x-ray absorptiometry (DEXA) scan showing osteopenia. Her history is significant for hypertension and chronic kidney
serum 25-hydroxyvitamin D level is 4 ng/mL (10 nmol/L). disease. Her only medication is amlodipine. She has never
She was started on 50,000 U of vitamin D2 (ergocalciferol) smoked.
78
Self-Assessment Test
On physical examination, temperature is 36.8 °c (98.3 °F), hot flushes and fatigue. She has noted galactorrhea. She
blood pressure is 134/87 mm Hg, pulse rate is 92/min, and began having headaches 2 years ago. In addition, she notes
respiration rate is 14/min. BM! is 27. The remainder of her blurry peripheral vision.
examination is unremarkable. The rest of her medical history is unremarkable. She
takes no medications.
Laboratory studies:
On physical examination, blood pressure is 112/72
Calcium 11.3 mg/dL (2.8 mmol/L)
1.3 mg/dL (114.9 µmol!L) mm Hg and pulse rate is 68/min. BMI is 21. White milky
Creatinine
76 pg/mL (76 ng/L) substance is expressed from her breasts bilaterally. Ocular
Parathyroid hormone
40 mL/min/1.73 m2 movements and cranial nerves are intact. There are no stig
Estimated glomerular
mata of Cushing disease or acromegaly.
filtration rate
Laboratory studies:
Dual-energy x-ray absorptiometry (DEXA) scan shows Cortisol 8 AM after 1 mg of 16 µg/dL (441.6 nmol/L)
a T-score of - 1.3 in the right femoral neck. Her Fracture dexamethasone the night
Risk Assessment Tool (FRAX) score indicates a 2.1% 10-year before
probability of hip fracture and 17% 10-year probability of Estradiol <32 pg/mL (117.4 pmol/L)
any fracture. Follicle-stimulating 1.1 mU/mL (1.1 U/L)
Which of the following is the most appropriate therapy to hormone
Luteinizing hormone 0.8 mU/mL (0.8 U/L)
recommend to this patient?
Prolactin 472 ng/mL (472 µg/L)
(A) Alendronate Thyroid-stimulating 1.1 µU/mL (1.1 mU/L)
(B) Cinacalcet hormone
(C) Parathyroidectomy MR! shows a 2.4-cm pituitary tumor that elevates the
(D) Clinical observation optic chiasm and surrounds the left carotid artery.
Which of the following is the most appropriate treatment?
Item 18 (A) Cabergoline
A 74-year-old woman is evaluated because of new-onset (B) Octreotide
anxiety and insomnia. For the last 6 weeks, she has been (C) Radiation
waking up multiple times each night. She does not have
(D) Surgery
heat intolerance, change in bowel habits, palpitations, or
dyspnea on exertion. She takes no medications.
Cl
On physical examination, blood pressure is 125/68 mm Item 20
Hg and pulse rate is 89/min. BM! is 18. There is no proptosis
A 74-year-old woman is evaluated in the emergency depart
or lid lag. Examination of the thyroid reveals a 1.5-cm firm
ment for several hours of' altered mental status. She is from
nodule in the left lobe that moves upward with swallowing.
out-of-state and is visiting with relatives. One of her young
A fine resting hand tremor is present bilaterally.
relatives was recently ill with gastrointestinal symptoms.
Laboratory studies reveal a serum thyroid-stimulat
The patient developed anorexia 3 days ago and vomiting
ing hormone level of 0.05 µU/mL (0.05 mU/L), a serum
2 days ago. She has been unable to tolerate any liquid or solid
free thyroxine (T,) level of 2.9 ng/dL (37.4 pmol/L), and
foods for the last 24 hours. Medical history is significant for
a serum total triiodothyronine (T) level of 250 ng/dL
Lype 2 diabetes rnellitus. hypertension. hyperlipidemia, and
(3.8 nmol/L).
hypothyroidism. Medications are aspirin. lisinopril. glime
Ultrasound of the neck shows two thyroid nodules, a
piride, levothyroxine, and atorvastatin. Her last dose of med
1.5-cm nodule in the right lobe and a 2.0-cm nodule in the
ications was 48 hours ago.
left lobe.
On physical examination, her temperature is 37.5 °C
Which of the following is the most appropriate next step in (99.5 °F). blood pressure is 115/65 mm Hg, and pulse
management? rate is 95/min. She is arousable but confused. Mucous
membranes are dry. Her neck is supple. Cardiac exam
(A) Fine-needle aspiration of both thyroid nodules ination reveals no murmurs. Her chest is clear Lo auscul
(B) Initiation of methimazole tation. Bowel sounds are present. and mild tenderness
(C) Radioactive iodine (123 1) uptake and scan of the thy Lo palpation is noted throughout the abdomen. ·n1ere is
roid no rebound or guarding. There are no focal neurologic
(D) Total thyroidectomy deficits.
Laboratory studies are pending.
Which of the following is the most likely cause of this
Item 19 patient's altered mental status?
A 34-year-old woman is evaluated for amenorrhea, head
(A) Cerebrovascular accident
ache, and fatigue. She reports that from the time of menarche
until 2.5 years ago, her menses were regular and predictable. (B) Hypoglycemia
Two and a half years ago, her menses became irregular and (CJ Hypothyroidism
then stopped completely 6 months ago. She has had a few (D) Slatin toxicity
79
Self-Assessment Test
Item 21 with a round face. She has terminal hairs on her chin, upper
A 38-year-old woman is evaluated because of a 3-week lip, chest, and back. Mild facial acne, central obesity, and a
history of palpitations. She notes that her heart "races" few wide purple striae on the back of her arms are also noted.
at night and after minimal exertion. She also report: l·�?t She has supraclavicular fat. Her skin has psoriatic plaques.
intolerance but has no change in bowel habits or menses. Muscle strength in the upper and lower extremities is 4/5.
On physical examination, the patient is restless and Which of the following is the most likely diagnosis?
has pressured speech. Temperature is 36.8 °c (98.2 °F),
blood pressure is 130/60 mm Hg, pulse rate in llO/min, and (A) Adrenocortical carcinoma
respiration rate is 12/min. Her skin is warm and moist, and (B) Cushing disease
a bilateral hand tremor is present. There is no proptosis or (C) Ectopic adrenocorticotropic hormone production
lid lag. The thyroid is enlarged without nodules or bruits. (D) Iatrogenic Cushing syndrome
Serum thyroid-stimulating hormone level is 0.08 µU/rnl
(0.08 mU/L), and the serum free thyroxine (T4) level is 1.7
ng/dL (21.9 pmol/L).
Which of the following is the most appropriate next step in
Item 24
A 20-year-old woman is evaluated in the emergency depart Cl
management? ment for polyuria. polydipsia, polyphagia. and an uninten
(A) Measure serum triiodothyronine (T) level tional 5.Ll-kg (ll.9-lb) weight loss over the past month.
She has had increasing lethargy over the last 24 hours. Her
(B) Measure serum thyroid peroxidase antibody titer
medical history and family history are unremarkable. She
(C) Repeat thyroid function tests in 6 weeks takes no medications.
(D) Schedule ultrasound of the neck On physical examination. temperature is 37.5 °C
(99.5 °F). blood pressure is 98/52111111 Hg, pulse rate is 120/
min. and respiration rate is 30/min. BMI is 17. She is lethar
Item 22 gic with dry mucous membrane . tachypnea, and tachy
A 34-year-old woman is evaluated for a diagnosis of hyper cardia. Chest auscultation is clear. Abdominal examination
calcemia after presenting to the emergency department 3 shows difl'use mild tenderness and normal bowel sounds.
days ago for treatment of a kidney stone. She presented with There is no rebound tenderness or guarding with palpation.
severe right flank pain with nausea and vomiting. A 2-mm Laboratory studies:
kidney stone was identified in the right ureter by ultraso Hemoglobin 17 g/dL (170 g/L)
nography that passed spontaneously; multiple additional Leukocyte count 14.200/�lL (14.2 x 10"/L)
intrarenal calcifications were noted to be present. Labora Blood gases. arterial
tory studies at that time showed normal kidney function pH 7.25
and a serum calcium level ofll .5 mg/dL (2.9 mmol/L). Med PCO., 21111111 Hg (2.8 kPa)
ical history is otherwise significant for hypertension and Creatinine 1.3 mgldL (114.9 µmollL)
sarcoidosis. Her only medication is hydrochlorothiazide. Electrolytes
On physical examination, temperature is 36.8 °C (98.2 °F), Sodiu111 130 mEq/L (13011111101/L)
blood pressure is 138/87 mm Hg, pulse rate is 89/min, and Potassium 3.0 mEqlL (3.011111101/L)
respiration rate is 12. BM! is 32. The remainder of the exam Chloride 99 mEq/L (99 mmol/L)
ination is unremarkable. Bicarbonate 9 mEq/L (9 11111101/L)
Laboratory studies are significant for a parathyroid Glucose 620 mg/dL (34.4 mmol/L)
hormone level of 4 pg/mL (4 ng/L). Lactic acid 8 mg/dL (0.89 mmol/L)
Which of the following is most likely responsible for caus Intravenous 0.9'Y., saline is initiated through a central
ing this patient's hypercalcemia? venous catheter.
(A) Calcium-sensing receptor mutation An electrocardiogram shows sinus tachycardia 120/min.
Chest radiograph is normal.
(B) Elevated 1,25-dihydroxyvitamin D levels
(C) 25-Hydroxyvitamin D level Which of the following is the most appropriate next step
(D) Thiazide-induced renal calcium reabsorption in the management?
(A) Administer intravenous ceftriaxone
(Fl) Administer intravenous potassium chloride
Item 23
(C) Administer intravenous sodium bicarbonate
A 40-year-old woman is evaluated for amenorrhea of 4 (D) Initiate intravenous insulin therapy
months' duration. She has had weight gain, facial hair,
alopecia, and debilitating fatigue. Her medical history is
significant for psoriasis. She seems to be gaining weight in
her face, abdomen, and neck. She also bruises easily. Her Item 25
only medication is clobetasol for psoriasis. A 65-year-old woman is evaluated following a recent diag
On physical examination, temperature is 37.6 °C nosis of osteoporosis discovered on a screening dual-energy
(99.7 °F), blood pressure is 148/90 mm Hg, pulse rate is 88/ x-ray absorptiometry (DEXA) scan that showed T-scores
min, and respiration rate is 12/min. BM! is 38. She is obese of -2.5 at the femoral neck and -2.7 at the hip. Overall she
80
Self-Assessment Test
feels well, although she notes a 5-cm (2-in) loss of height striae measuring 8 to 12 mm wide are noted on his upper
over the past 15 years and a 2.3-kg (5-lb) weight loss over arms and abdomen. There isl+ bilateral lower extremity
the last year. She is postmenopausal. Medical history is edema. Multiple ecchymoses and acanthosis nigricans
unremarkable, and she is a never-smoker. Family history are present.
is negative for osteoporosis or nontraumatic fractures. She Laboratory studies:
takes no medications. Adrenocorticotropic <5 pg/mL (1.1 pmol/L)
On physical examination, temperature is 36.8 °c hormone
(98.2 °F), blood pressure is 144/68 mm Hg, pulse rate is 92/ 24-Hour urine cortisol
min, and respiration rate is 14/min. BM! is 22. The remainder excretion
of the examination is unremarkable. Initial measurement 280 µg/24 h (771.6 nmol/24 h)
Laboratory studies are significant for a normal basic Repeat measurement 300 µg/24 h (826.7 nmol/24 h)
metabolic profile and complete blood count. Serum calcium Cortisol, serum 46 µg/dL (1269.6 nmol/L)
is 9.5 mg/dL (2.4 mmol/L) and serum phosphorus is 3.8 mg/ Urine
dL (1.2 mmol/L). Serum 25-hydroxyvitamin D level is 32 ng/ Catecholamines 40 µg/m2/24 h (236.4 nmol/m2/
dL (79.9 nmol/L). 24 h)
Which ofthe following tests is indicated prior to initiation Metanephrines 1000 µg/24 h (5070 nmol/24 h)
ofpharmacologic therapy?
CT scan of the abdomen with and without contrast
(A) Serum and urine markers of bone turnover reveals a 5.6-cm heterogeneous right adrenal mass with
(B) Serum estradiol level focal areas of calcifications and hemorrhage. The density of
(C) Serum parathyroid hormone level the mass is SO Hounsfield units, and the contrast washout
at 10 minutes is 20%.
(D) Serum thyroid-stimulating hormone level
Which ofthe following is the most appropriate next step in
the management ofthis patient's adrenal mass?
Item 26
(A) Chemotherapy
A 24-year-old woman is evaluated for excessive men
strual bleeding. She was recently diagnosed with polycys (B) Fine-needle biopsy
tic ovary syndrome during an evaluation for hirsutism. (C) Radiation therapy
Menarche occurred at age 11 years, and she has always (D) Surgical excision
had irregular menses occurring approximately every 60
days. However, her periods over the past year have been
associated with heavy bleeding that is increasingly both
ersome. Medical history is otherwise unremarkable, and
Item 28
/1. 47-year old man presents to the emergency department CJ
she takes no medications. She currently does not desire with weakness and shakiness. I-le has a long history ofalco
fertility. hol abuse but significantly decreased his usual daily alcohol
On physical examination, she is afebrile. Blood pres int<1ke over the past week because of gastrointestim1I upset.
sure is ll0/70 mm Hg, pulse rate is 78/min, and respiration nausea. and diarrhea. Medical history is ol hcrwise unre
rate is 14/min. BM! is 32. Excess terminal hair growth is markable. and he takes no medications.
present on the upper lip, chin, and chest. The physical On physical examination. the patient is awake and
examination is otherwise normal. oriented but tremulous. Mucous membranes are dry.
A urine pregnancy test is negative. Temperature is 37.:3 °C (99.1 °F). blood pressure is 139 76
111111 I lg, pulse rate is IOI/min. and respiration rate is IS
Which ofthe following is the most appropriate therapy for min. f3MI is 19. Cardiopulmonary examination is unre
this patient? mark<1ble. The abdomen is diffusely tender lo palpation.
(A) Combined oral contraceptive pills Periodic spontaneous twitching is noted in the major
(B) Levonorgestrel intrauterine system muscle groups.
Laboratory studies arc signifkanl for a serum cal
(C) Metformin
cium level or 6.5 mg di. (1.6 mmol/1.). serum albumin
(D) Periodic progestin withdrawal level of 2.6 g/dL (26 g/L). serum potc1ssium or 3.4 mEq/L
(:l.4 mmol/L). and norm,11 kidney runction studies. Serum
Item 27 parathyroid hormone and 25 hydroxyvitamin D levels
are pending.
A 55-year-old man is evaluated for abdominal fullness and An electrocardiogram shows prolongation or the QT
nausea of 2 weeks' duration. He has no vomiting or fever. interval.
One month ago, he was diagnosed with type 2 diabetes
mellitus. He reports an unintentional weight loss ors kg (11 Which of"the following is the most appropriate next diag
lb) over the past month, generalized weakness, and poor nostic test to evaluate this patient's hypocalcemia?
appetite. Metformin is his only medication. (A) l.25-Dihydroxyvitamin D level
On physical examination, blood pressure is 158/90
mm Hg and pulse rate is 90/min. BM! is 29. His face (B) 24-l-lour urine calcium cxcretion
is round and red. A dorsocervical fat pad is present. (C) Ionized calcium level
His abdomen is distended, but nontender. Violaceous (D) Magnesium level
81
Self-Assessment Test
82
Self-Assessment Test
83
Self-Assessment Test
Laboratory studies are significant for a serum calcium serum cortisol following a low-dose overnight dexameth
level ofll .2 mg/dL (2.8 mmol!L), parathyroid hormone level asone suppression test. Subsequent testing revealed a sup
of 55 pg/mL (55 ng/L), and 25-hydroxyvitamin D level of 35 pressed adrenocorticotropic hormone level.
ng/mL (87.4 nmol!L). Kidney and thyroid function studies A contrast-enhanced adrenal CT scan revealed a
are normal. well-circumscribed 3.7-cm right adrenal mass with a con
trast washout of greater than 50% at 10 minutes.
Which of the following is the most appropriate next step in
management? Which of the following is the most appropriate perioper
ative management?
(A) Bone densitometry
(B) Measurement of urine calcium and creatinine levels (A) Postoperative hydrocortisone
(C) Parathyroid sestamibi scan (B) Postoperative mitotane
(D) Referral for parathyroidectomy (C) Postoperative norepinephrine
(D) Preoperative phenoxybenzamine
Item 38
A 25-year-old woman with type 1 diabetes mellitus is eval Item 40
uated for recent-onset glycemic fluctuations without symp A 62-year-old man is evaluated for right leg pain. The pain
tomatic hypoglycemia. She was diagnosed with diabetes 7 has developed progressively over the past 6 months and
years ago. Her hemoglobin A1c levels since diagnosis have worsens with prolonged activity, such as playing golf. Med
ranged from 6.4% to 7.3%, with the most recent value at ical history is unremarkable, and he takes no medications.
7.3%. She reports eating a carbohydrate-consistent diet at On physical examination, temperature is 36.3 °C (97.3 °F),
each meal, with little variation in her selection of meals blood pressure is 128/67 mm Hg, pulse rate is 73/min, and
or snacks. She started a new job several months ago but respiration rate is 10/min. BMl is 29. There is no pain to
continues her daily exercise routine and sleep schedule. She palpation over the femoral region, and he has normal range
has no other medical problems or symptoms. Her diabetes of motion.
treatment regimen is insulin glargine once daily and insulin Laboratory studies are significant for a serum alkaline
lispro three times daily. phosphatase level of 200 U/L and serum calcium level of 9.0
Physical examination findings and vital signs are nor mg/dL (2.3 mmol!L).
mal. Plain radiograph of the right femur is shown.
Estimate glomerular filtration rate, serum creatinine
level, and urine albumin-creatinine ratio are normal. Her
blood glucose values from the previous week are shown
below.
Blood glucose values:
Breakfast Lunch Dinner Bedtime
(mg/dL (mg/dL (mg/dL (mg/dL
[mmol!L]) [mmol/L]) [mmol!L]) [mmol!L])
124 (6.9) 190 (10.5) 109 (6.1) 210 (11.6)
110 (6.1) 92 (5.1) 112 (6.2) 126 (7.0)
115 (6.4) 118 (6.5) 112 (6.2) 126 (7.0)
117 (6.5) 127 (7.0) 204 (11.3) 110 (6.1)
108 (6.0) 101 (5.6) 122 (6.8) 114 (6.3)
101 (5.6) 111 (6.2) 106 (5.9) 72 (4.0)
126 (7.0) 187 (10.4) 102 (5.7) 196 (10.9)
84
Self-Assessment Test
Item 41 Item 43
A 29-year-old woman is evaluated during her first prenatal A 44-year-old woman is evaluated for weight gain, muscle
visit. She feels well. Medical history is significant only for weakness, and metabolic syndrome. She has hirsutism but
hypothyroidism, for which she has taken levothyroxine, also notes hair loss on her head. She has been amenorrheic
100 µg/d, for the last 3 years. Her only other medication is a for 2 years.
prenatal vitamin. Medical history is significant for hyperlipidemia, type
On physical examination, she is afebrile. Blood pres 2 diabetes mellitus, hypertension, and obesity. Medications
sure is 98/72 mm Hg, pulse rate is 88/min, and respiration are atorvastatin, metformin, and lisinopril.
rate is 12/min. The thyroid is of normal size and without On physical examination, blood pressure is 156/92 mm
nodules. There is no cervical lymphadenopathy. Cardio Hg and pulse rate is 78/min. BM! is 42. She has a cushingoid
vascular and pulmonary examinations are unremarkable. appearance, acne, and moderate hirsutism affecting the chin,
Abdominal examination reveals normal bowel sounds. The upper lip, breasts, back, and chest. There are several wide vio
uterus is not palpable. laceous striae across the abdomen and the back of her arms.
Laboratory studies show a serum thyroid-stimulating Laboratory studies:
hormone level of 3.6 µU/mL (3.6 mU/L) and a serum total Adrenocorticotropic 52 pg/mL (11.4 pmol/L)
thyroxine (T4) level of 4.5 µg/dL (58 nmol/L). hormone (ACTH)
Which of the following is the most appropriate treatment of Cortisol 8 AM after 1 mg of 5.2 µg/dL (143.5 nmol/L)
this patient's hypothyroidism? dexamethasone the night
before
(A) Continue levothyroxine dose 24- Hour urine cortisol
(B) Decrease levothyroxine dose excretion
(C) Discontinue levothyroxine Initial measurement 124 µg/24 h (341.7 nmol/24 h)
Repeat measurement 98 µg/24 h (270.0 nmol/24 h)
(D) Increase levothyroxine dose
lntrapetrosal sinus sampling identifies a pituitary
microadenoma as the source of the high ACTH level.
Item 42 Which of the following is the most appropriate test to per
A 62-year-old man is evaluated in the hospital for several form next?
hours of nausea. lightheadedness. and back and abdominal
pain. He underwent uncomplicated mechanical aortic valve (A) 8-mg dexamethasone suppression test
replacement 3 days ago. He had been doing well postop (B) 24-Hour urine free catecholamine and metanephrine
eratively until the development of his current symptoms. measurement
Medical history is significant only for hypothyroidism. Med (C) Dual-energy x-ray absorptiometry scan
ications are therapeutic unfractionated heparin, levothy (D) PETscan
roxine. and as-needed oxycodone.
On physical examination. temperature is 37.2 °C
(99.0 °F), blood pressure is 80/50 111111 Hg. pulse rate
Item 44
is 110/rnin, and respiration rate is 1 8/min. BMI is 26.
Examination of the chest shows a clean and dry sternal A 28-year-old woman is being discharged from the hospital
wound. Cardiac examination reveals regular tachycar with a diagnosis of autoimmune adrenalitis. Medical history
dia and mechanical S.,. There is no pain with palpation is otherwise unremarkable. and she was on no medications
of the abdomen or lov\rer back. His skin pigmentation is prior to admission.
normal. On physical examination. temperature is 37.0 °C (98.6 °F).
blood pressure is 120/80 mm Hg. pulse rate is 80/min. and
Laboratory studies: respiration rate is 12/min. BMI is 22. Increased skin pigmen
Hemoglobin 7.3 g/dL (73 g/1.) tation is noted over the extensor surfaces of the extremities
9.0 g/dL (90 g/1.) bilaterally. Tl1e remainder of" her examination is normal.
postoperatively
Leukocyte count 11.000/µL (II x 10''/i.) Which of the following is the most appropriate long-term
Activated partial 70 s medication regimen for this patient?
thromboplastin time
1.0 mg/dL (88.4 µmol/L) (A) Dexamethasone. I mg once daily
Creatinine
Sodium 130 mEq/L (130 mrnol/L) (B) Fludrocortisone. 0.05 mg once daily
Potassium 6.0 mEq/L (6.0 mmol/U (C) Hydrocortisone.10 mg three times daily
Cortisol, random <2 µg/dL (55.2 nmol/L) (D) Prednisone, 5 mg once daily. and fludrocortisone.
0.05 mg once daily
Which of the following is the most likely diagnosis?
(A) Autoimmune adrenalitis Item 45
(BJ Bilateral adrenal hemorrhage A 78-year-old woman is evaluated for a 2-week history of
(C) Opiate-induced adrenal insun'iciency unintentional weight loss, night sweats, and neck swelling.
(D) Pituitary apoplexy She has more recently also had difficulty swallowi11g solid
85
363
Self-Assessment Test
foods and positional shortness of breath. She does not have Which of the following is the most appropriate manage
hoarseness, palpitations, or change in bowel habits. Prior ment of this patient?
to the development of these symptoms, she had been in her
(A) Refer for parathyroidectomy
usual state of health with no illnesses. She has hypothyroid
ism and has been taking levothyroxine for 40 years, with a (B) Start alendronate
stable dose for the past 10 years. (C) Start calcitonin
On physical examination, temperature is 36.9 °c (98.4 °F), (D) Start cinacalcet
blood pressure is 140/88 mm Hg, pulse rate is 75/min, and (E) Start vitamin D3 (cholecalciferol)
respiration rate is 12/min. Tile thyroid is symmetrically
enlarged, firm, and fixed. 1here is no thyroid bruit.
CT scan of the neck is shown. Item 47
A 57-year-old man is ad111itted to the hospital for evaluation Cl
of' substernal chest pain. His medical history is significant
f'or type 2 diabetes 111ellitus. coronary artery disease, hyper
tension. and hyperlipide111ia. He manages his diabetes as
an outpatient with diet. exercise, and 111etfor111in. His other
111edications are aspirin. metoprolol. atorvastatin. and sub
lingual nitroglycerin as needed. His inpatient plas111a glu
cose values are 170 to 210 111g/dL (9.4-11.6 rnmol!L). Results
of'all other laboratory studies are normal.
Which of the following is the most appropriate treatment
for this patient's diabetes while hospitalized?
(A) Basal and prandial insulin
(13) Glipizicle
(C) Metf'or111in
(D) Slicling-scale insulin
Item 48
Which of the following is the most likely diagnosis? A 43-year-old woman is evaluated for progressive weight
(A) Graves disease gain over the past 2 years. Her previous weight was 72.6 kg
(160 lb) but has steadily risen to her current weight of 106.6
(B) Papillary thyroid cancer kg (235 lb). She notes a slight increase in her appetite but
(C) Primary thyroid lymphoma minimal change in her lifestyle or activity level. She has
(D) Subacute thyroiditis tried to lose weight with increased exercise and nutritional
counseling but without significant results. More recently
she reports having trouble sleeping and decreased exercise
Item 46 tolerance with activites such as walking up steps. Medical
A 67-year-old man is evaluated for a recent diagnosis of history is significant for impaired fasting glucose, hyper
primary hyperparathyroidism after an elevated serum cal tension, and hyperlipidemia. Medications are hydrochlo
cium level was incidentally detected on laboratory testing. rothiazide and atorvastatin. She has not been prescribed
Medical history is significant only for hypertension, and his glucocorticoids or had glucocorticoid joint injections.
only medication is ramipril. On physical examination, temperature is 37.2 °C (99.0 °F),
On physical examination, temperature is 35.8 °C (96.4 °F), blood pressure is 136/86 mm Hg, pulse rate is 88/min, and
blood pressure is 120/68 mm Hg, pulse rate is 62/rnin, and respiration rate is 12/min. BM! is 38. She has rounded facies,
respiration rate is 14/rnin. BM! is 32. 1he remainder of his thin hair, mild hirsutism, and prominent fat deposition in
examination is unremarkable. the dorsocervical and supraclavicular areas. Her skin is thin,
Laboratory studies: and she bruises easily, although striae are not present. Her
Calcium 10.9 mg/dL (2.7 mmol/L) examination is otherwise unremarkable.
Creatinine 0. 9 mg/dL (79.6 µmol/L) Laboratory studies are significant for a fasting plasma
Parathyroid hormone 98 pg/mL (98 ng/L) glucose level of 120 mg/dL (6.7 mmol/L) and normal thy
25-Hydroxyvitamin D 19 ng/mL (47.4 nmol/L) roid-stimulating hormone level.
Estimated glomerular >60 mL/min/1.73 m2 Which of the following is the most appropriate next step in
filtration rate
evaluation?
A dual-energy x-ray absorptiometry (DEXA) scan (A) Adrenocorticotropic hormone measurement
shows T-scores of -1.3 in the right femoral neck, -1.0 in the (13) 1-mg dexamethasone suppression test
lumbar spine, and -1.4 in the non-dominant forearm. Frac
ture Risk Assessment Tool (FRAX) score indicates a 13% risk (C) 8-mg dexarnethasone suppression test
of major osteoporotic fracture and a 1. 9% risk of hip fracture (D) Pituitary MRI
over the next 10 years. (E) Serum cortisol measurement
86
Self-Assessment Test
Item 49 Item 51
A SO-year-old man undergoes follow-up evalua A 64-year-old man with type 2 diabetes mellitus and stage 4
tion for type 2 diabetes mellitus. His daily log demon chronic kidney disease is evaluated for continued glycemic
strates average blood glucose levels of 120 to 150 mg/dL management. He is followed closely by the nephrology ser
(6.7-8.3 mmol!L), with hypoglycemia in the 50 mg/ vice in preparation for impending hemodialysis, with initi
dL (2.8 mmol/L) range noted once or twice per week ation of erythropoietin therapy within the last 3 months. His
without a discernible pattern. He is unable to detect the average fasting and preprandial blood glucose values are in
hypoglycemia. the 145 to 190 mg/dL (8.0-10.5 mmol/L) range. He does not
The patient has a medical history of diabetic ret have hypoglycemia. His insulin regimen consists of insulin
inopathy, chronic kidney disease, peripheral neurop detemir at bedtime and insulin glulisine before meals. His
athy, hypertension, hyperlipidemia, obstructive sleep most recent hemoglobin A1e value has decreased from 7.5%
apnea (on bilevel positive airway pressure), gastro to 6.2%.
esophageal reflux disease, and osteoarthritis in both
Which of the following is the most appropriate manage
knees. He reports intolerance to strenuous exercise due
ment for this patient's diabetes?
to knee pain. He is able to walk 15 minutes daily. He has
worked closely with a nutritionist, resulting in a 5.0- (A) Continue current therapy
kg (11-lb) weight loss over 1 year, which has plateaued (B) Decrease insulin detemir dose
recently. (C) Discontinue preprandial insulin glulisine
Medications are insulin glargine, insulin aspart, lis
inopril, carvedilol, pantoprazole, aspirin, and atorvas (D) Measure postprandial glucose level
tatin.
On physical examination, blood pressure is 140/
90 mm Hg and pulse rate is 65/min. BM! is 37. Bilateral Item 52
proliferative retinopathy is present. There are no carotid A 34-year-old woman is evaluated for hirsutism and acne
bruits or cardiac murmurs. Bilateral loss of monofilament that began 4 months ago. She also reports that her voice
and vibratory sensation on the feet and decreased ankle has become deeper. Her menstrual periods have remained
reflexes are noted. The remainder of the examination is regular, occurring every 28 days.
normal. She has one son 5 years of age. She reports that her
Results of laboratory studies show hemoglobin pregnancy was uncomplicated and she had no difficulty
A1e level of 8.2% and serum creatinine level of 1.7 mg/dL conceiving. She had a tubal ligation following the birth of
(150.3 µmol/L). her child. She has a sister with polycystic ovary syndrome.
She takes no medications.
Which of the following is the most appropriate treatment
On physical examination, blood pressure is 140/84 mm
of this patient?
Hg, and pulse rate is 62/min. BM! is 21. She has hyperpig
(A) Bariatric surgery mented terminal hairs on the chin, neck, abdomen, and
(B) Increase insulin lower back and comedones and pustules on the face and
(C) upper back. There is frontotemporal hair loss. The remain
Initiate metformin
der of the examination is unremarkable.
(D) Initiate pramlintide
Laboratory studies:
Cortisol, free (urine) 26 µg/24 h (71.6 nmol/24 h)
Dehydroepiandrosterone 8.2 µg/mL (22.1 µmol/L)
Item 50 sulfate
A 47-year-old woman is evaluated for an incidentally dis Prolactin 8 ng/mL (8 µg/L)
covered right adrenal mass. Testosterone 96 ng/dL (3.3 nmol/L)
On physical examination, blood pressure is 120/80 mm
Hg in both arms and pulse rate is 84/min. The abdomen is
Which of the following is the most appropriate diagnostic
nontender, and there are no palpable masses. The remain test to perform next?
der of the examination is unremarkable.
Noncontrast CT of the abdomen demonstrates a 3.2-cm (A) Abdominal CT scan
well-circumscribed, partially cystic right adrenal lesion (B) Low-dose dexamethasone suppression test
with a density of 30 Hounsfield units. A low-dose dexa (C) Pelvic ultrasound
methasone suppression test is negative for evidence of cor
(D ) Pituitary MRI
tisol hypersecretion.
Which of the following is the most appropriate next step in
management? Item 53
(A) Adrenalectomy A 27-year-old woman is evaluated for management of her
(B) type 1 diabetes mellitus. She was diagnosed 10 years ago. She
CT-guided transcutaneous biopsy
has no known complications from her diabetes. She eats a
(C) Plasma aldosterone to plasma renin ratio healthy diet and exercises an average of 60 minutes per day in
(D) Plasma free metanephrines the evening. She takes insulin glargine and insulin aspart. She
(E) No additional testing is indicated is adherent with her insulin regimen and checks her blood
87
Self-Assessment Test
glucose level three to five times per day. Her average blood erections but reports low libido and occasional erectile dys
glucose value is 125 mg/dL (6.9 mmol/L), with fasting glucose function during intercourse. He wakes once during the night
values ranging from 80 to 150 mg/dL (4.4-8.3 mmol/L). She to urinate and drink water. He estimates that he urinates 5 to
routinely measures her 2-hour postprandial glucose values, 8 times during the day, which is unchanged.
and they are consistently less than 150 mg/dL (8.3 mmol/L). Medical history is significant for transsphenoidal
She has several overnight blood glucose values ranging from resection of a craniopharyngioma at age 18 years. He has
90 to 140 mg/dL (5.0-7.8 mrnol/L). Her hemoglobin A 1c values required anterior pituitary hormone replacement and des
over the last 6 months have been 7.3% to 7.5%. She is discour mopressin since that time. Medications are desmopressin,
aged that her hemoglobin A 1c values remain above 7.0%. hydrocortisone, levothyroxine, somatropin, and testoster
Laboratory studies, including creatinine and complete one enanthate.
blood count, are normal. On physical examination, temperature is 37.0 °C (98.6 °F),
blood pressure is 118/64 mm Hg, pulse rate is 74/min, and
Which of the following is the most appropriate manage
respiration rate is 14/min. No orthostatic changes are noted.
ment of her elevated hemoglobin A1 c level?
BM! is 24. There are no facial changes suggestive of acromeg
(A) Begin continuous glucose monitoring aly or Cushing syndrome. The thyroid is normal without
(B) Increase exercise goiter or nodules. Hair distribution and skin turgor are
normal. There is no gynecornastia or striae. Normal penis
(C) Increase insulin aspart
and testicular volume are noted. Visual fields are intact on
(D) Increase insulin glargine neurologic examination.
Laboratory studies:
Item 54 Sodium 138 mEq/L (138 mmol!L)
Insulin-like growth factor 1 Normal
A 25-year-old woman is evaluated after a recent diagnosis of Prolactin 18 ng/mL (18 µg/L)
polycystic ovary syndrome. She is concerned about hirsut 1hyroid-stimulating hormone 0.8 µU/mL (0.8 rnU/L)
ism and irregular menses. She has no desire to be pregnant Thyroxine (T), free 0.7 ng/dL (9.0 pmol!L)
at this time. She takes no medications. Testosterone (11 days after 482 ng/dL (16.7 nmol!L)
On physical examination, she is afebrile. Blood pres injection)
sure is 110/60 mm Hg, pulse rate is 68/min, and respiration
rate is 16/min; BM! is 37. Coarse hair is noted on the chin, Follow-up MR!s show no residual tumor.
jawline, and periumbilical area. The remainder of her phys
ical examination, including pelvic examination, is normal. Which of the following is the most appropriate manage
ment?
Which of the following is the most appropriate treatment?
(A) Increase desmopressin
(A) Combined oral contraceptive pills (B) Increase hydrocortisone
(B) Intermittent progestin withdrawal (C) Increase levothyroxine
(C) Levonorgestrel intrauterine system (D) Increase testosterone enanthate
(D) Spironolactone therapy (E) Stop somatropin
Item 55 Item 57
A 46-year-old man is evaluated following a diagnosis of pheo A 55-year-old man is evaluated following a screening for
chromocytoma. He has no signs or symptoms at this time. type 2 diabetes mellitus. He is asymptomatic. He has a his
Except for hypertension, his medical history is unremark tory of hypertension and hyperlipidemia. 1here is no history
able. Medications are lisinopril and hydrochlorothiazide. of anemia, liver disease, or kidney disease. Medications are
On physical examination, blood pressure is 170/90 mm lisinopril and rosuvastatin.
Hg and pulse rate is 90/min. The remainder of the physical On physical examination, blood pressure is 123/
examination is unrevealing. 76 mm Hg and pulse rate is 72/min. BM! is 28. The remainder
of the examination is unremarkable.
Which of the following is the most appropriate next step in
management? Laboratory studies:
Hematocrit 45.6%
(A) Increase lisinopril dosage Creatinine 1.0 mg/dL (88.4 µmol/L)
(B) Perform contrast-enhanced adrenal CT scan Glucose, fasting 128 mg/dL (7.1 mmol/L)
(C) Start phenoxybenzamine Hemoglobin A,c 5.6%
(D) Start propranolol
Which of the following is the most appropriate diagnostic
test to perform next?
Item 56
(A) Fasting plasma glucose
A 38-year-old man with panhypopituitarism is evaluated for
worsening fatigue and weight gain over the past 3 months. He (B) Hemoglobin A,c
is sleeping 9 hours each night, but he feels tired during the day (C) Oral glucose tolerance test
and has decreased h.is usual exercise level. He has morning (D) Random blood glucose
88
Self-Assessment Test
Item 59
Item 61
An 84-year-old man is evaluated for moderate fatigue. He
otherwise feels well and does not have constipation, cold A 68-year-old man is seen in follow-up for a recent diagno
intolerance, weight gain or loss, anxiety, tremor, palpita sis of acromegaly. He presented with chronic fatigue, joint
tions, or dyspnea. Medical history is significant for hyper and back pain, and an increase in his shoe size over the past
tension, and his only medication is felodipine. 2 years. Medical history is significant for hypertension and
On physical examination, he is alert and oriented. Blood type 2 diabetes mellitus. Current medications are lisinopril,
pressure is 144/83 mm Hg; other vital signs are normal. The rnetformin, and as-needed acetaminophen.
thyroid is not palpable. Cardiopulmonary examination is On physical examination, blood pressure is 146/88 mm
normal. TI1ere is no peripheral edema. Neurologic examina Hg and pulse rate is 90/min. BM! is 29. He has a prominent
tion is nonfocal, and deep tendon reflexes are normal. brow. Macroglossia is present. Lung and heart examinations
are unremarkable. Musculoskeletal examination reveals
Laboratory studies:
large hands and knees with bone swelling and crepitus.
Complete blood count Normal Skin is thickened, and there is excessive perspiration. On
Comprehensive metabolic Normal neurologic examination, bitemporal hemianopsia is noted.
profile Laboratory studies are significant for an elevated serum
TI1yroid-stimulating hormone 6.4 µU/mL (6.4 mU/L} insulin-like growth factor 1 level of 996 ng/mL (996 µg/L}
(TSH)
and serum prolactin level of 42 ng/rnL (42 µg/L}.
Free thyroxine (T,) 1.3 ng/dL (16.8 pmol/L} MRI shows a 2.5 x 1.8-cm pituitary macroadenoma that
elevates the optic chiasm and appears to envelop the left
Which of the following is the most appropriate manage carotid artery and invade the left cavernous sinus. TI1e optic
ment? chiasm is mildly atrophied.
(A) Levothyroxine therapy Which of the following is the most appropriate next step in
(B) Measurement of serum total triiodothyronine (T3) therapy for this patient?
level
(A) Dopamine agonist
(C) Measurement of serum total T,1 level
(B) Growth hormone receptor blockade
(D) Repeat TSH and free T4 measurement in 6 to 12 weeks
(C) Somatostatin analogue
(D) Stereotactic radiation therapy
Item 60 (E) Transsphenoidal pituitary surgery
A 62-year-old woman is evaluated for an incidentally dis
covered left adrenal mass. Two weeks ago, the patient was
evaluated in the emergency department for diffuse abdom Item 62
inal pain and vomiting. A CT scan was obtained that was A 47-year-old man is evaluated postoperatively following
normal except for the adrenal mass. TI1ree hours after pre thyroidectomy for papillary thyroid cancer. Preoperative
sentation to the emergency department, the pain resolved evaluation showed no evidence of distant metastatic dis
spontaneously. ease, and he underwent total thyroidectomy with central
89
Self-Assessment Test
and left lateral neck dissections. The patient's medical his Which of the following is the most appropriate treatment?
tory is otherwise unremarkable.
(A) Clomiphene citrate
On physical examination, vital signs are normal. The
neck surgical sites are clean and dry. The remainder of the (B) In vitro fertilization
examination is unremarkable. (C) Injectable gonadotropin
The surgical pathology report reveals a 3.5-cm papillary (D) Metformin
thyroid cancer in the left lobe of the thyroid and six malig
nant lymph nodes out of 35 dissected. There is evidence of
minor extrathyroidal extension and vascular invasion by Item 65
the primary tumor. A 64-year-old woman is seen for follow-up evaluation. Two
Which of the following is the most appropriate postopera weeks ago, she was in a car accident, and an incidental pitu
tive treatment? itary adenoma was found on a cervical spine CT scan. She
has no residual injuries from the car accident.
(A) Doxorubicin chemotherapy She is otherwise healthy and takes no medications. She
(B) External-beam radiotherapy went through menopause at age 51. She has night sweats
(C) Radioactive iodine therapy two to three times per month and occasional hot flushes.
(D) No additional therapy These have improved over the past decade and are not
bothersome. She is not sexually active. She has never taken
hormone replacement therapy. She has had no change in
vision, headaches, or galactorrhea.
Item 63
On physical examination, temperature is 37.5 °C
A 66-year-old man is evaluated in the office after being (99.5 °F), blood pressure is 110/63 mm Hg, pulse rate is
treated in the emergency department for an exacerbation of 82/min, and respiration rate is 14/min. BM! is 26. There
chronic obstructive pulmonary disease. While in the emer is axillary and pubic hair loss. Visual fields are intact.
gency department, he was noted to have a random blood There are no findings suggestive of Cushing syndrome or
glucose level of 211 mg/dL (11.7 mmol/L). His hemoglobin acromegaly.
A,c was 7.8% at the time. A repeat random fingerstick blood
Laboratory studies:
glucose level in office is 204 mg/dL (11.3 mmol/L).
Estradiol <20 pg/mL (73.4 pmol!L)
The patient reports recent polyuria and polydipsia. He
Follicle-stimulating hormone 6.4 mU/mL (6.4 U/L)
has lost 6 kg (13.2 lb) over the last 3 months. He has chronic
Luteinizing hormone 3.2 mU/mL (3.2 U/L)
epigastric pain associated with loose, oily stools due to
Prolactin 53 ng/mL (53 µg/L)
chronic pancreatitis.
Thyroid-stimulating hormone 3.2 µU/mL (3.2 mU/L)
He has a 20-pack-year history of tobacco use and
l11yroxine (T), free 1.1 ng/dL (14.2 pmol!L)
prior alcohol use, however, he does not currently use alco
hol. Current medications are enteric-coated pancreatic Pituitary MRI shows a 7-mm adenoma in the anterior
enzymes, vitamins, tiotropium inhaler, and an albuterol sella. The tumor is not invasive. It does not approximate the
inhaler as needed. optic chiasm. The pituitary stalk is mid-line.
On physical examination, temperature is 37.1 °C (98.8 °F),
blood pressure is 130/75 mm Hg, and pulse rate is 90/min. Which of the following is the most appropriate manage
BM! is 22. He has mild epigastric pain on palpation without ment?
rebound tenderness or guarding. The rest of his examination (A) Begin dopamine agonist
is unremarkable.
(B) Gamma knife stereotactic radiosurgery
Which of the following is the most appropriate treatment (C) Repeat testing in 12 months
for his diabetes? (D) Transphenoidal resection
(A) Exenatide
(B) Glipizide
Item 66
(C) Insulin
(D) Metformin A 57-year-old man with a 15-year history of type 2 diabe
tes mellitus is evaluated for bilateral burning sensation in
his feet for the last 6 to 12 months. The sensation worsens
at night. His hemoglobin A 1 c levels have remained less
Item 64 than 7.0% for the last 2 years but were between 8.0% and
A 34-year-old woman is evaluated because she and her male 9.0% before implementing significant lifestyle changes
partner have been trying to conceive for 13 months without and transitioning to insulin therapy from metformin ther
success. Her medical history is notable for a 6-year history apy 2 years ago.
of irregular menses and a recent diagnosis of polycystic His medical history includes coronary artery disease,
ovary syndrome. Her only medication is a prenatal vitamin. first-degree atrioventricular block, nonproliferative dia
On physical examination, vital signs are normal. BM! is betic retinopathy, hypertension, and hyperlipidemia.
36. Terminal hair growth on the chin, upper lip, and sides Medications are regular insulin, neutral protamine
of the face is noted. No evidence of abdominal or pelvic Hagedorn (NPH) insulin, aspirin, metoprolol, atorvastatin,
masses, clitoromegaly, or galactorrhea is detected. and lisinopril.
90
Self-Assessment Test
On physical examination, findings are compatible with rate is 16/min. BM! is 24. Pelvic examination reveals a non
distal polyneuropathy. tender, mobile uterus.
Which of the following is the most appropriate manage Laboratory studies:
ment of this patient's neuropathy? Estradiol <80 pg/mL (293.6 pmol/L)
Follicle-stimulating hormone 6.2 mU/mL (6.2 U/L)
(A) Amitriptyline Luteinizing hormone 4.1 mU/mL (4.1 U/L)
(B) Duloxetine Prolactin Normal
(C) Nerve conduction study Thyroid-stimulating hormone Normal
(D) Vitamin B 12 measurement Urine human chorionic Negative
gonadotropin
CJ Item 67
A 72-year-olcl man presents to the emergency department
Which of the following is the most appropriate diagnostic
test to perform next?
overnight. His wife noted that he was cliaphoretic and
(A) MRI of the pituitary
restless during the night, and his initial blood glucose level
measured by emergency medical services was 41 mg/ell (B) Peripheral karyotype
(2.3 mmol/L). He was given a single dose of' intravenous (C) Progestin withdrawal test
glucose, which increased his blood glucose level to 85 mg/ell (D) Transvaginal ultrasound
(4.7 mmol/L). His symptoms recurred en route to the hos
pital, and he responded to a second dose of' intravenous
glucose. While in the emergency department, he was Item 69
provided food and his glucose level has remained above A 29-year-old woman comes to the office for a follow-up
80 mg/dL (4.4 mmol/L) without further treatment. The evaluation. She was diagnosed with type 2 diabetes mellitus
patient ·s wife reports several recent episodes or overnight 2 years ago. Her fasting and premeal blood glucose values
diaphoresis over the last several weeks. His last meal range from 120 to 150 mgidL (6.7-8.3 mmol/L). She has had
prior to this episode was approximately 7 hours before no hypoglycemic events. She has been adherent with her
symptom onset. insulin regimen along with diet and exercise modifications.
His medical history is significant for hypertension and Her hemoglobin A,c level has decreased from 9.0% to 7.5%
osteoarthritis. Medications are lisinopril and as-neeclecl ibu over the last 12 months. She expresses frustration over the
profen. need for multiple medications to treat her diabetes. Medical
On physical examination. the patient is alert and ori history is otherwise unremarkable.
ented. Blood pressure is 135/84 mm Hg, and pulse rate is 82/ Medications are insulin glargine, insulin aspart, and
min. BMI is 23. ll1e general physical and neurologic exam metformin.
inations are normal. On physical examination, blood pressure is 120/72 mm
Laboratory studies are significant for a normal com Hg and pulse rate 80/min. BM! is 27. The remainder of the
plete metabolic profile and blood count. An insulin secre examination is normal.
tagogue screen is obtained. and hypoglycemic studies con Hemoglobin A,c level is currently 7.4%. Results of all
sisting of measurement of insulin, C-pepticle. proinsulin. other laboratory studies are normal.
and �-hydroxybutyrate levels are planned.
Which of the following is the most appropriate manage
Which of the following is the most appropriate diagnostic ment of this patient's diabetes?
strategy for this patient?
(A) Increase insulin glargine dose
(A) Hypoglycemic studies now (B) Measure 3 AM blood glucose level
(B) Mixed-meal testing with hypoglycemic studies at the (C) Measure postprandial blood glucose levels
time of symptomatic hypoglycemia (D) Switch metformin to sitagliptin
(C) Oral glucose tolerance testing with hypoglycemic
studies at the time of symptomatic hypoglycemia
(D) 72-Hour fast with hypoglycemic studies at the time Item 70
or symptomatic hypoglycemia A 32-year-old woman is evaluated for a 2-week history of
foreign body sensation in her eyes. Despite flushing the eyes
numerous times with saline, the sensation remains. She also
Item 68 feels pressure behind her eyes. She is not pregnant. Medical
A 24-year-old woman is evaluated for a 3-month history of history is unremarkable.
amenorrhea accompanied by cyclic pelvic pain. Preceding On physical examination, scleral injection and peri
the onset of amenorrhea, she had a recent dilatation and orbital edema are present bilaterally, right worse than left.
curettage to remove retained products of conception after Diplopia is noted on lateral gaze. There is no lid lag or
a first-trimester spontaneous abortion. Her personal and proptosis. ll1e thyroid is diffusely enlarged, and a bruit is
family medical history is unremarkable. She takes no med noted. Neurologic examination discloses brisk reflexes and
ications. a bilateral hand tremor.
On physical examination, she is afebrile. Blood pres Laboratory studies reveal a serum thyroid-stimulating
sure is 110/60 mm Hg, pulse rate is 68/min, and respiration hormone level of less than 0.008 µU/mL (0.008 mU/L), a
91
Self-Assessment Test
Item 71
A 42-year-old man is evaluated for resistant hypertension.
He was diagnosed with hypertension at age 35 years and
reports that his blood pressure has never been well con
trolled. He is taking his medications as prescribed. He does
not have headaches, chest pain, palpitations, shortness of
breath, or symptoms of panic attack. He has no history of TI1ere is diffuse enlargement of the thyroid, and the
cardiovascular disease, does not smoke, and does not drink inferior edge of the gland cannot be visualized. CT scan
alcohol. Medications are lisinopril, amlodipine, hydrochlo shows substernal extension of the goiter in the left lobe
rothiazide, metoprolol, and potassium chloride supplemen with mild tracheal narrowing and tracheal deviation to
tation. He is not taking any over-the-counter medications. the right.
On physical examination, blood pressure is 150/86 mm Which of the following is the most appropriate treatment?
Hg and pulse rate is 65/min. BM! is 24. Examination of the
heart is significant for an S,1 but no murmurs. TI1e remainder (A) External-beam radiotherapy
of his examination is unremarkable. (B) Levothyroxine
Laboratory studies are significant for a serum creati (C) Radioactive iodine
nine level of 1.0 mg/dL (88.4 µmol/L), fasting plasma glu
(D) TI1yroidectomy
cose level of 82 mg/dL (4.5 mmol/L), and serum potassium
level of3.2 mEq/L (3.2 mmol/L).
Which of the following is the most appropriate next d.iag Item 73
nostic step? A 26-year-old woman is evaluated because she and her
(A) Dexamethasone suppression test husband have been trying to conceive for 14 months with
out success. Her husband fathered a child in a previous
(B) Plasma aldosterone-plasma renin activity ratio marriage. Her medical history is notable for pelvic inflam
(C) Plasma metanephrines and catecholamines matory disease, which was diagnosed and successfully
(D) Renal artery Doppler flow study treated at age 18 years. Her only medication is a prenatal
vitamin.
Physical examination findings are unremarkable.
Item 72
Which of the following studies is most likely to be diag
A 65-year-old man is evaluated because of painless neck
nostic?
swelling and difficulty swallowing that has progressively
worsened over the last year. He does not have hoarseness, (A) Diagnostic laparoscopy
but he feels as though his voice is not as strong as it was in (B) Hysterosalpingogram
the past. Medical history is significant for multiple thyroid (C) Peripheral karyotype of the patient
nodules. Fine-needle aspiration of three of the largest nod
ules 5 years ago showed that all nodules were benign on (D) Semen analysis of the patient's husband
cytologic examination. Medical history is otherwise unre (E) Transvaginal ultrasound assessment of follicle count
markable, and he takes no medications.
On physical examination, vital signs are normal. ·n1e
thyroid is diffusely enlarged and mobile with swallowing. Item 74
He has facial flushing when raising his hands above his head A 46-year-old man is evaluated for a right lateral neck mass.
as shown (see top of next column). He first noted the mass while shaving 2 weeks ago. He does
No cervical lymphadenopathy is noted. Cardiovascular not have hoarseness or difficulty swallowing. Medical his
and pulmonary examinations are normal. Reflexes are nor tory is significant only for hypertension. His only medica
mal, and there is no visible tremor. tion is hydrochlorothiazide.
Laboratory studies show a serum thyroid-stimulating On physical examination, blood pressure is 165/95 mm
hormone (TSH) level of 4.0 µU/mL (4.0 mU/L). Hg, pulse rate is 88/min, and respiration rate is 12/min.
Thyroid ultrasound shows innumerable coales TI1ere is a firm 2-cm mass in the right lateral neck and a
cent nodules with no suspicious sonographic features. mobile 1-cm right thyroid nodule.
92
Self-Assessment Test
Laboratory studies: ranging from 50 to 190 mg/dL (2.8-10.5 mmol/L). His over
Calcium 10.5 mg/dL (2.6 mmol/L) night blood glucose values range from 120 to 140 mg/dL
Creatinine 1.8 mg/dL (159.1 µmol/L) (6.7-7.8 mmol/L). He is unable to detect hypoglycemia.
Thyroid-stimulating 4.8 µU/mL (4.8 mU/L) The patient is concerned about hyperglycemia, and he
hormone desires to reach a hemoglobin A,c level of less than 7%.
Medical history is significant for diabetic retinopathy,
Ultrasound of the neck reveals a hypoechoic thyroid peripheral neuropathy, hypertension, and hyperlipidemia.
nodule with microcalcifications measuring 1.6 cm. There is Medications are neutral protamine Hagedorn (NPH) insulin,
a 2.2-cm mass with internal calcifications in the area of the regular insulin, losartan, chlorthalidone, metformin, rosu
palpable abnormality. vastatin, and aspirin.
Fine-needle aspiration of the thyroid nodule and the On physical examination, blood pressure is 125/82
lateral neck mass reveals medullary thyroid cancer. RET mm Hg and pulse rate is 80/min. BM! is 24. Retinal
testing is positive for a mutation in codon 634. examination demonstrates nonproliferative retinopa
Which of the following is the most appropriate next step in thy. His lower extremities have diminished sensation
management? to a 10-g monofilament and vibration with a 128-Hz
tuning fork.
(A) 18-Fluoro-deoxyglucose positron emission tomogra- Hemoglobin A,c level is 7.2%, and the results of all other
phy scan laboratory studies are normal.
(B) Plasma fractionated metanephrine levels
Which of the following is the most appropriate treatment of
(C) Serum parathyroid hormone level this patient's diabetes?
(D) Total thyroidectomy and lateral neck dissection
(A) Continue current insulin and metformin doses
(B) Continue current insulin, increase metformin dose
CJ Item 75 (C)
(D)
Decrease meal-time insulin, add pramlintide
Decrease meal-time insulin, continue metformin
A 55-year-old woman is evaluated in the emergency
department for altered mental status that has developed
over the past week. Her family notes that she has become Item 77
increasingly confused, and her oral intake has decreased
signiflcantly. Her medical history includes breast cancer A 28-year-old woman is evaluated for a 6-month history of
that was diagnosed s years ago. Additional medical his infertility. In order to predict her fertile period, the patient
tory is significant for hypertension. Her only medication is has been using a home urinary luteinizing hormone (LH)
chlorthalidone. kit. The kit can identify an LH surge and therefore predict
On physical examination, the patient is minimally ovulation and the optimal time for intercourse. Her uri
responsive. Mucous membranes are dry. Temperature is nary LH kit result has been consistently positive but her
36.2 °C (97.2 °F). blood pressure is 100/59 111111 Hg. pulse pregnancy test result consistently negative. She has been
rate is l lO/min, and respiration rate is 12/min. BM! is 22. exercising recently in an attempt to lose weight. Her med
There is mild, difluse abdominal tenderness to palpation. ical history is otherwise unremarkable, and she takes no
The remainder of the examination is unremarkable. medications.
Laboratoty studies are significant for a serum sodium On physical examination, vital signs are normal. BMI is
level or 148 mEq/L (l48 mmol/L). creatinine level or 38. Coarse terminal hairs are noted on the chin, neck, and
4.0 mg/dL (353.6 µmol/L). baseline creatinine level is anterior chest. Pelvic examination is normal.
1.6 mg/dL (141.4 µmol/L), and calcium level of 18.2 mg/dL Pelvic ultrasound reveals a thickened endometrium
(4.6 mmol/L). and polycystic-appearing ovaries bilaterally.
Chlorthalidone is discontinued. and intravenous nor Which of the following is the most likely diagnosis?
mal saline is started.
(A) Hypothyroidism
Which of the following is the most appropriate immediate
(B) Late-onset congenital adrenal hyperplasia
next step in management?
(C) Polycystic ovary syndrome
(A) Calcitonin (D) Prolactinoma
(B) Cinacalcet
(C) Hemodialysis
Item 78
(D) Zoledronic acid
A 72-year-old woman is evaluated in follow-up for oste
oporosis. Medical history is significant for a hip fracture
5 years ago sustained after a mild fall. Evaluation at that
Item 76 time included a dual-energy x-ray absorptiometry (DEXA)
A 60-year-old man is evaluated during a routine follow-up scan showing a left hip T-score of -2.8 and vertebral
examination. He has type 2 diabetes mellitus. Review of T-score of -2.7. She has been maintained on alendronate
his blood glucose log demonstrates fasting blood glucose therapy since that time. Medical history is also significant
values ranging from 120 to 160 mg/dL (6.7-8.9 mmol/L) for hypertension. Medications are alendronate, hydro
and variable 2-hour postprandial blood glucose values chlorothiazide, calcium, and vitamin D. Family history
93
Self-Assessment Test
is significant for osteoporosis in her mother, sister, and On physical examination, her temperature is 37.2 °C
maternal aunt. She has a 35-pack-year tobacco use history (99.0 °F), blood pressure is 118/68 mm Hg, pulse rate is
and continues to smoke. 72/min, and respiration rate is 10/min. BM! is 28. Other
On physical examination, temperature is 36.9 °c wise, her physical examination is unremarkable.
(98.4 °F), blood pressure is 138/87 mm Hg, pulse rate is Laboratory studies:
89/min, and respiration rate is 12/min. BM! is 28. She Human chorionic gonadotropin Negative
has marked thoracic kyphosis and increased central Prolactin 68 ng/mL (68 µg/L)
adiposity. TI1yroid-stimulating hormone 15 µU/mL (15 mU/L)
Laboratory studies show a serum calcium level of TI1yroxine (T4), free 0.82 ng/dL (10.6 pmol/L)
8.6 mg/dL (2.2 mmol/L) and 25-hydroxyvitamin D level
of 44 ng/mL (109.8 nmol/L); kidney function studies are
normal. Which of the following is the most appropriate manage
Repeat DEXA shows a stable bone mineral density. ment?
Which of the following is the most appropriate treatment of (A) Begin cabergoline
this patient's osteoporosis? (B) Begin levothyroxine
(C) Hold sertraline and retest
(A) Change to denosumab
(D) Order pituitary MRI
(B) Change to teriparatide
(C) Continue alendronate therapy
(D) Initiate a drug holiday
Item 81
A 33-year-old man is evaluated for infertility. As part of
Item 79 this evaluation, azoospermia is identified on two sequential
A 55-year-old man presents for follow-up of a recent diag semen analyses. His medical history is otherwise notable for
nosis of hyperaldosteronism. Medical and family history chronic sinusitis. He takes no medications.
are unremarkable. Medications are losartan, metoprolol, On physical examination, vital signs are normal. BM!
amlodipine, and chlorthalidone. is 24. There is no evidence of inguinal hernia. A small left
On physical examination, blood pressure is 150/90 mm sided varicocele is present that empties when the patient is
Hg and pulse rate is 70/min. TI1e rest of the examination is recumbent. Testicles are of normal size. Absence of the vas
unremarkable. deferens is noted bilaterally.
Additional studies include a noncontrast CT scan of the
Which of the following is most likely responsible for this
abdomen that shows a 1.2-cm homogeneous left adrenal
patient's infertility?
lesion with a density of -5 Hounsfield units. Adrenal vein
sampling indicates similar ratios of aldosterone to cortisol (A) Anabolic steroid abuse
bilaterally. (B) Cystic fibrosis
Which of the following is the most appropriate therapy for (C) Klinefelter syndrome
this patient? (D) Varicocele
(A) Bilateral adrenalectomy (E) Y chromosome microdeletions
(B) Dexamethasone
(C) Left adrenalectomy
(D) Spironolactone Item 82
A 22-year-old woman is evaluated for fatigue and weight
loss over the last 2 months. She describes a lack of energy,
Item 80 decreased appetite, and an unintentional 3.6-kg (8-lb)
A 24-year-old woman is evaluated for 3 months of galac weight loss. Over the last week she has experienced nau
torrhea, worsening fatigue, and malaise. She was well sea and occasional vomiting. She notes no other focal
6 months ago and without explanation began feeling symptoms. She has no significant medical history. Family
tired and lethargic. She has noted milk leaking sponta history is remarkable for hypothyroidism in her mother
neously from her breasts. Her menses have been unpre and type 1 diabetes mellitus in her brother. She takes no
dictable. She had a normal cycle 3 months ago and medications.
4 months ago, but then her next cycle was delayed. Her On physical examination, temperature is normal,
last menstrual period was 6 weeks ago, and she had blood pressure is 100/68 mm Hg, pulse rate is 90/min, and
excessive bleeding. She has stopped exercising and has respiration rate is 12/min. BM! is 19. Hyperpigmentation
gained 3.6 kg (8 lb). She also reports headaches that is pronounced over the knuckles of the hands and elbows
occur about 2 to 3 times per week. She has noted consti bilaterally. The remainder of the physical examination is
pation and breast tenderness. She has no libido, which unremarkable.
is a significant change. She took a home pregnancy test, Laboratory evaluation demonstrates an 8 AM serum
which was negative. She has a history of depression. cortisol level of 2 µg/dL (55.2 nmol/L), a serum sodium
There is no family history of pituitary disease. Her only level ofl33 mEq/L (133 mmol/L), and a serum potassium
medication is sertraline for depression. level of 5.8 mEq/L (5.8 mmol/L).
94
Self-Assessment Test
Which of the following is the most appropriate next step in (C) Discontinue insulin glargine, change insulin aspart to
management? a sliding-scale regimen
(A) Cosyntropin stimulation test (D) Discontinue insulin glargine, discontinue insulin
aspart
(B) Hydrocortisone and fludrocortisone
(C) Plasma adrenocorticotropic hormone (ACTH) mea
surement
Item 84
(D) Prednisone
A 34-year-old man is evaluated for a 1-year history
of decreased libido and severe erectile dysfunction,
Item 83 including absence of morning erections. He and his
A 21-year-old woman is evaluated for management of type female partner would like to conceive. His medical
1 diabetes. She was diagnosed 3 months ago after presenting history is otherwise unremarkable, and he takes no
to the emergency department with diabetic ketoacidosis. medications.
Her hemoglobin A1e level at the time of diagnosis was 15.2%. On physical examination, vital signs are normal. BM! is
She was discharged from the hospital on a basal and pran 27. Atrophic testes are noted bilaterally.
dial insulin regimen with minor adjustments required as Laboratory studies:
an outpatient. Her blood glucose log demonstrates a recent Follicle-stimulating hormone 1.2 mU/mL (1.2 U/L}
change manifesting as frequent symptomatic episodes of Luteinizing hormone 0.8 mU/mL (0.8 U/L}
both fasting and postprandial hypoglycemia with blood glu Prolactin llO ng/mL (llO µg/L}
cose levels ranging from SO to 65 mg/dL (2.8-3.6 mmol/L}. Morning testosterone (total) 120 ng/dL (4.2 nmol/L}
Medications are insulin glargine and insulin aspart. Thyroid-stimulating hormone Normal
On physical examination, blood pressure is ll0/70 mm
Hg and pulse rate is 70/min. BM! is 19. The remainder of the MRI of the pituitary reveals a 0.8-cm anterior pituitary
examination is unremarkable. mass consistent with an adenoma.
Hemoglobin A 1e level is 6.2%. Which of the following is the most appropriate
Which of the following is the most appropriate manage treatment?
ment for this patient's hypoglycemia? (A) Cabergoline
(A) Decrease insulin glargine, decrease insulin aspart (B) Clomiphene citrate
(B) Decrease insulin glargine, decrease insulin aspart, add (C) Sildenafil
pramlintide (D) Testosterone replacement therapy
95
Answers and Critiques
97
Answers and Critiques
_ _
than 200 ng/mL (200 µg/L). Additionally, this patient has a measuring the glucose level at 3 AM. Medications that affect
known prolactinoma. so her prolactin will likely be elevated the overnight glucose level need to be decreased if the 3 AM
for both reasons. Elevated prolactin itself is not necessarily glucose level is low. Medications that affect the overnight
harmful. Prolactinomas cause concern when they cause glucose should be increased or added if the 3 AM glucose level
hypogonadism or mass effect. ln this patient, an elevated is elevated.
prolactin level will not change the treatment plan because it Fast-acting insulin such as insulin lispro at bedtime
is expected to be elevated and does not help clarify whether increases the risk of hypoglycemia.
the prolactinoma is causing harm. Metformin will decrease gluconeogenesis from the liver
Routine monitoring of women with prolactinomas with and improve fasting hyperglycemia. However, for similar
MRI during pregnancy is not indicated because the absolute reasons, overnight hypoglycemia must be excluded before
risk of significant enlargement of pituitary adenomas is this treatment could be safely initiated.
low. However, MRI is indicated in women with a pituitary Increasing the insulin glargine dose could also worsen
macroadenoma and abnormalities on visual field testing or overnight hypoglycemia if that is the cause of the fasting
change in headache possibly attributable to expansion of the hyperglycemia.
adenoma. Despite the hemoglobin A 10 level of less than 7%, the
Bromocriptine is avoided in pregnancy when possible etiology of the patient's fasting hyperglycemia should be
because its safety during gestation has not been established, investigated. Detection of overnight hypoglycemia would
although when a patient has symptoms of mass effect during necessitate immediate changes in her insulin regimen or
pregnancy, bromocriptine may need to be restarted. How food intake regardless of her hemoglobin A 10 value.
ever, it would not be appropriate to restart dopamine agonist
KEY POINT
therapy in this patient without a clear indication for treat
ment such as an enlarging pituitary adenoma. • Overnight blood glucose monitoring can help detect
hypoglycemia or dawn phenomenon.
KEY POINT
Bibliography
Melmed S. Casanueva FF, Hoffman AR. et al. Diagnosis and treatment of
hyperprolactinemia: an Endocrine Society clinical practice guideline. J Item 5 Answer: A
Clin Enclocrinol Metab. 2011 Feb:96(2):273-88. [PMID: 21296991) Educational Objective: Evaluate the cause of Cushing
syndrome.
98
Answers and Critiques
dexamethasone suppression test (LOST) (both standard and development of ketoacidosis, which would require restarting
overnight), 24-hour urine free cortisol (UFC), or late-night insulin therapy.
salivary cortisol. This patient failed to suppress cortisol levels Determining autoimmunity, in conjunction with beta
following an overnight LOST and had an elevated 24-hour cell function, is helpful in assessing whether a patient has
UFC level confirmed by a repeat collection. Therefore, the potential to become insulin-independent in the future.
measurement of late night salivary cortisol is unnecessary His autoantibodies were negative at the time of his presen
because the diagnosis of CS has already been established. tation, and it is unlikely that these would now be positive. It
KEY POINT
is not necessary to retest antibodies in this setting.
Bibliography Bibliography
Nieman LK. Biller BM. Findling JW. et al. The diagnosis of Cushing·s Maldonado MR. Otiniano ME, Cheema F. et al. Factors associated with insu
syndrome: an Endocrine Society Clinical Practice Guideline. J Clin lin discontinuation in subjects with ketosis-prone diabetes but preserved
Endocrinol Metab. 2008 May:93(5):1526-40. [PMID: 18334580] �-cell function. Diabet Med. 2005 Dec:22(12):1744-50. [PMID: 16401322]
ltem6 Answer: D
Educational Objective: Manage ketosis-prone type 2
Item 7 Answer: C
Educational Objective: Treat pituitary apoplexy.
Cl
diabetes mellitus. The patient has acute apoplexy caused by pituitary hemor
This patient should have a repeat measurement of fast rhage and requires urgent transsphenoidal decompression
ing C-peptide and glucose levels. He has ketosis-prone of the hemorrhage Lo preserve vision. Given his history of
type 2 diabetes mellitus. Patients with ketosis-prone type previous headache, loss of I ibiclo. and erectile dysfunction.
2 diabetes do not fulfill the classic phenotype associated he likely had a preexisting prolactinoma that acutely bled.
with autoimmune type 1 diabetes. These patients are often Prolactinomas are almost always treated wilh dopamine ago
older, overweight or obese, and of black or Latino ethnic nisls. but this patient requires urgent surgery to decrease
ity. Patients with new-onset ketosis-prone diabetes require pressure on Lhe optic chiasm to save his vision. Transsphe
insulin therapy initially but might be able to be managed noidal resection is the preferred method of pituitary surgery.
with oral agents in the future. Prior to switching from He also requires urgent stress dose glucocorticoids because
insulin to oral therapy, his pancreatic beta-cell function of risk of' secondary cortisol deficiency, which would be
should be assessed with fasting C-peptide and glucose mea lifc-Lhreatcning.
surements. Ketosis-prone type 2 diabetes is heterogeneous ·1 he patient has appropriately received glucoconicoids
condition in that the presence of autoantibodies is variable fcir possible adrcnoconicot ropic hormone deficiency. -r here
across the population, as is the degree of pancreatic beta cell is no indication to assess other pituitary function. In the
function. His initial C-peptide level in the setting of hyper next 2 Lo 4 weeks. thyroid f'unction will need to be assessed.
glycemia and diabetic ketoacidosis is not an accurate indi but thyroxine Cl) has a long half' life and does not need to
cation of his pancreatic function. Due to the toxic effects be emcrgently measured or replaced. Tr·eatment or hypogo
of prolonged hyperglycemia on the pancreatic beta cells, naclism or growl h hormone deficiency is not urgent: surgical
the fasting C-peptide and glucose or a glucagon-stimulated decompression is.
C-peptide should be measured 7 to 14 days after the correc Waiting 2 weeks Lo rcpcat imaging could lead to per
tion of the acidosis in order to better assess function. If his mancnt vision loss. I le needs immediate intervention Lo
repeat fasting C-peptide value is greater than or equal to 1.0 preserve his vision. Similarly. whole brain external beam
ng/mL (0.33 nmol/L) or his glucagon-stimulated C-peptide raclialion is not appropriate fi>r this patient who needs rapid
value is greater than or equal to 1.5 ng/mL (0.5 nmol!L), his surgic.1 I decompression.
beta cell function is preserved. KEY POINT
A sliding-scale insulin regimen that does not include
• Patients with pituitary apoplexy and vision loss
basal insulin and does not begin insulin administration
should receive immediate stress-dose glucocorticoids
unless the blood glucose level is at or above a threshold level
in addition to undergoing urgent transsphenoidal
will cause wide swings from hyperglycemia to hypoglyce
pituitary decompression.
mia, and this is inappropriate treatment.
Discontinuation of his insulin and switching to an oral
agent such as metformin could be attempted with evidence Bibliography
Rajasekaran S. Vanderpump M. Baldeweg S. et al. UK guidelines for the
of beta cell function preservation. Close follow-up would management of pituitary apoplexy. Clin Endocrinol. 2011 Jan;74(1):9-20.
be necessary to monitor for worsening hyperglycemia or [PMID: 21044119]
99
Answers and Critiques
100
Answers and Critiques
101
Answers and Critiques
weight-bearing exercise and avoidance of tobacco or excessive occur during an acute illness is lowering or the serum total
alcohol) in addition to calcium and vitamin D supplementa triiodolhyronine (T.) level. 1l1e serum thyroid-stimulating
tion is appropriate management of this patient. hormone (TSH) and serum free thyroxine (T) levels may also
Raloxifene is a selective estrogen receptor modulator decline as the illness increases in severity. '!he pattern of these
(SERM) that is a treatment option for women with osteo test results is often indistinguishable from that seen with
porosis because it has been shown to increase bone mineral ccntra I hypothyroidism. In fact. some con Lroversy exists about
density and reduce the risk of vertebral (but not nonverte whether the clinical picture of' a low sernrn TSH level and low
bral) fractures. However, raloxifene is also associated with serum T 1 and T� levels is an adaptive response to the critical
an increased risk of thromboembolic events and vasomotor illness in order to alter the body's metabolism and thereby aid
symptoms. There is limited data supporting use of raloxifene in recovery from the acute illness.
or other SERMs for treating patients with low bone mass, ·111is patient does not have any definite findings of
although some guidelines recommend considering treat underlying Graves disease. 1l1e tachycardia and fever are
ment in patients with low bone mass and 10-year fracture likely the result of his severe infection. If' he was also
risk determined by the FRAX calculator of greater than or experiencing thyroid storm, high serum T I and T3 levels
equal to 20% for a major osteoporotic fracture or greater than would most likely be associated with the low serum TSH
or equal to 3% for hip fracture. Raloxifene would therefore concentration.
not be appropriate therapy for this patient. ·n,e most common cause of hypothyroidism is
Cholecalciferol (D), a metabolite of vitamin D, is com Hashimoto thyroiditis. Physical examination findings can
monly used to supplement low serum vitamin D levels in include a reduced basal temperature. diastolic hypertension.
patients with vitamin D deficiency. This patient has normal an enlarged thyroid gland. bradycardia. p,1llor. dry and cold
serum vitamin D levels; therefore, there is no indication for skin, brittle hair. hoarseness. and a delayed recovery phase
treatment with vitamin D metabolites. of deep tendon renexes. Patients with Hashimoto thyroiditis
Bisphosphonates are considered first-line therapy for have low T.1 and T.1 levels and elevated TSH. This patient's
osteoporosis, although they are not used routinely in women low TSH level is not compatible with Hashimoto thyroiditis.
with low bone mass. Similar to the use of SERM therapy, TI1is patient is unlikely to have subacute thyroiditis
guidelines recommend consideration of treatment with a based on the timing of the illness. Although the infection
bisphosphonate for low bone mass only if there is 10-year could have triggered destruction of the thyroid. the subse
fracture risk determined by the FRAX calculator of greater quent release of preformed thyroid hormones into the serum
than or equal to 20% for a major osteoporotic fracture or should result in an elevation of serum T4 and T1 levels in the
greater than or equal to 3% for hip fracture. early phase of the disease. which is not consistent with the
findings in this case.
KEY POINT
women involves lifestyle modification (maximizing • Unless there is a strong suspicion of an underlying
weight-bearing exercise and avoidance of tobacco or thyroid disorder that may be contributing to a
excessive alcohol) and vitamin D and calcium supple patient's clinical findings, thyroid function tests
mentation; the need for pharmacologic therapy is should not be performed during critical illness
based on the 10-year estimated fracture risk (:2'.20% for because test results are highly likely to be abnormal.
a major osteoporotic fracture or :2'.3% for hip fracture).
Bibliography
Bibliography Farwell AP. Nonthyroidal illness syndrome. Curr Opin Endocrinol Diabetes
Obes. 2013 Oct:20(5):478-84. [PMID: 23974778]
Kling JM. Clarke BL. Sandhu NP. Osteoporosis prevention, screening. and
treatment: a review. J Womens Health. 2014 Jul:23(7):563-72. [PMID:
24766381]
Item 14 Answer: B
Educational Objective: Liberalize glycemic targets in
Cl Item 13 Answer: A
Educational Objective: Diagnose euthyroid sick
a patient with multiple diabetic complications and
advanced microvascular disease.
syndrome.
1l1e most appropriate next step in management of this
-111is paliem·s clinical picture is consistent with euthyroid patient is to decrease the risk of hypoglycemia by decreas
sick syndrome (also called nonthyroidal illness syndrome). ing the insulin doses delivered by the pump. This patient
Unless there is a strong suspicion of an underlying thyroid has had type 1 diabetes for 25 years with subsequent devel
disorder that may be contributing to a patient's clinical find opment of advanced microvascular disease. His frequent
ings. lhyroid function tests should not be performed during hypoglycemic events and hypoglycemic unawareness
critical illness. In hospitalized patients. especially ones as ill increase the risk of morbidity and mortality from recur
as the patient described here. thyroid function test results rent hypoglycemia that may occur with stringent glycemic
are highly likely to be abnormal. The first deviation that may goals. Glycernic goals should be individualized to account
102
Answers and Critiques
for patient-specific factors, such as age and comorbidities. Parathyroid imaging with a sestamibi scan is not indi
The American Diabetes Association suggests a hemoglo cated because the patient does not have primary hyper
bin A 1 e goal of less than 8.0% in patients with a decreased parathyroidism. Her parathyroid hormone level is elevated
life expectancy, history of severe hypoglycemia, multiple as an appropriate physiologic response to her markedly
comorbidities, or advanced microvascular or macrovascular low vitamin D levels. Once her vitamin D levels are suffi
disease. lhe less stringent hemoglobin A1 e goal should be cient (>30 ng/dL [75 nmol!L]), her parathyroid hormone
implemented to avoid recurrent hypoglycemia; however, level should be remeasured to ensure that it has returned to
the goal may need to be increased above 8.0% if it cannot the normal range. lhe parathyroid hormone level should be
be achieved safely. remeasured in approximately 4 weeks.
Altering the pump settings to deliver more insulin to Referral for parathyroidectomy would also not be indi
attain a hemoglobin A1e goal of less than 7.0% will increase cated in this patient without an established diagnosis of
his risk of hypoglycemia. His hemoglobin A1e goal should be primary hyperparathyroidism.
liberalized to avoid hypoglycemia. A person her age with normal diet and minimal sun
The risk of hypoglycemia can be reduced with lower exposure should require about 1000 U daily of vitamin D to
insulin doses delivered by either an insulin pump or sub maintain adequate vitamin D stores. The choice to use chole
cutaneous injections. Since the patient is already using an calciferol versus ergocalciferol is often based on the level of
insulin pump, alteration of his insulin pump settings to vitamin D deficit. Since the ergocalciferol is more readily
deliver less insulin should occur next. available in the 50,000 U form and has a shorter half-life, it
Gabapentin for treatment of his painful peripheral neu is recommended when a patient's vitamin D level is less than
ropathy is appropriate, but avoidance of recurrent hypogly 10 ng/mL (25 nmol/L). Cholecalciferol is often used when
cemia is the most serious issue that needs to be addressed the level is between 20 and 30 ng/mL (50-75 nmol/L) or for
next due to the associated increased risk of morbidity and maintenance and therefore would not be ideal to replete this
mortality. patient. Clinical discretion can be used for levels between 10
and 20 ng/mL (25-50 nmol!L).
KEV POINT
Although vitamin 03 (cholecalciferoi) is a reasonable
• A less stringent hemoglobin A1 e goal is appropriate for option for treatment of vitamin D deficiency, as mentioned
persons with diabetes mellitus with a decreased life above, cholecalciferol is best used for maintenance of vita
expectancy, history of severe hypoglycemia, multiple min D levels or repletion when the 25-hydroxyvitamin
comorbidities, or advanced rnicrovascular or macro D level is between 20 ng/mL (50 nmol/L) and 30 ng/mL
vascular disease. (75 nmol/L). Neither form of repletion, however, will be
effective in the presence of significant malabsorption.
Bibliography
KEV POINT
American Diabetes Association. (6) Glycemic targets. In: Standards of
Medical Care in Diabetes-2015. Diabetes Care. 2015 Jan:38 Suppl l:S33- • When vitamin D repletion efforts fail, secondary
40. [PMID: 255377051
causes, such as malabsorption, should be considered.
Bibliography
Item 15 Answer: D
Tavakkol A. DiGiacorno D. Green PH, Lebwohl B. Vitamin D status and con
Educational Objective: Determine causes of vitamin comitant autoimmunity in celiac disease. J Clin Gastroenterol. 2013
Jul:47(6):515-9. [PMID: 23328299]
D deficiency.
103
Answers and Critiques
Graves disease cannot be made clinically in a patient with A bisphosphonate, such as alendronate, would not be
hyperthyroidism, measurement of the serum level of these the treatment of choice for this patient as she does not
antibodies is recommended, especially if radioactive iodine have osteoporosis nor does she meet Fracture Risk Assess
uptake studies are not available or if radioactive iodine expo ment Tool (FRAX) criteria for therapy. 1he FRAX calculator
sure is contraindicated, as in pregnancy and breastfeeding. defines the 10-year fracture risk for patients with T -scores
This patient does not have hyperthyroidism, and these tests in the -1.0 to -2.5 range. The FRAX calculator (www.shef.
are therefore not indicated. ac.uk/FRAX) incorporates multiple risk factors including
Repeating a serum TSH measurement in this patient gender, fracture history, femoral neck bone mineral den
was reasonable, since up to 30% of patients with an initially sity, glucocorticoid usage, smoking, BM!, age, and alcohol
abnormal serum TSH level will have a normalization of intake to determine projected fracture risk. If the risk of
this value upon retesting. Since this patient has persistent major osteoporotic fracture is greater than or equal to 20%
elevation of TSH and symptoms that may be attributable to or the risk of hip fracture is greater than or equal to 3%,
hypothyroidism, waiting 12 months before initiating therapy the patient's benefit from therapy exceeds the risk, and she
is not appropriate. should be offered treatment. Additionally, bisphosphonates
A radioactive iodine uptake (RAJU) scan is reserved for should be used with caution in patients with compromised
patients with hyperthyroidism. Patients with Graves disease kidney function.
typically have an elevated RAJU. Conversely, in patients with If the patient declines surgical intervention, a calci
thyroiditis or exposure to exogenous thyroid hormone, the mimetic agent such as cinacalcet would be an appropriate
RAJU will be low (<5%) despite biochemical hyperthyroid therapy. Cinacalcet has recently been FDA approved as an
ism. Obtaining a thyroid RAJU in this patient is not indicated. alternative for patients unable or unwilling to undergo para
thyroidectomy. Cinacalcet lowers calcium levels by stimulat
KEY POINT
ing the calcium-sensing receptors of the parathyroid glands
• Levothyroxine therapy is reasonable in a patient with and inhibiting parathyroid hormone secretion. However, it is
subclinical hypothyroidism and symptoms suggestive expensive and has multiple drug interactions, which make it
of hypothyroidism. less desirable in this patient.
Because this patient is considered to be at increased risk
Bibliography of complications due to untreated hypercalcemia, clinical
Garber JR. Cabin RH. Gharib H. et al; American Association of Clinical observation alone would not be appropriate.
Endocrinologists and American Thyroid Association Taskforce on
Hypothyroidism in Adults. Clinical practice guidelines for hypothyroid KEY POINT
ism in adults: cosponsored by the American Association of Clinical
Endocrinologists and the American Thyroid Association. Endocr Pract. • D ecreased estimated glomerular filtration rate (<60
2012 Nov-Oec:18(6):988-1028. Erratum in: Endocr Pract. 2013 Jan
Feb;l9(l):175. [PMID: 23246686] mL/min/1.73 m2) is an indication for surgical treat
ment of primary hyperparathyroidism in otherwise
asymptomatic persons.
Item 17 Answer: C
Bibliography
Educational Objective: Define surgical indications for Bilezikian JP, Brandi ML. Eastell R, Silverberg SJ. Udelsman R. Marcocci C,
primary hyperparathyroidism. et al. Guidelines for the Management of Asymptomatic Primary
Hyperparathyroidism: Summary Statement from the Fourth
The most appropriate treatment recommendation for this International Workshop. J Clin Endocrinol Metab. 2014;99(10):3561-9.
[PMIO: 251626651
patient is parathyroidectomy. She has primary hyperpara
thyroidism as shown by her elevated serum calcium and
parathyroid hormone levels. She also has evidence of kidney Item 18 Answer: C
compromise with an elevated creatinine level and decreased
Educational Objective: Evaluate a toxic thyroid nodule.
estimated glomerular filtration rate (eGFR). Impaired kid
ney function (defined as eGFR <60 mL/min/1.73 m2 , 24-h Performing a radioactive iodine (123 1) uptake and scan is the
urine calcium >400 mg/24 h [10 mmol/24 h], or the presence most appropriate management for this patient, who most
of nephrolithiasis or nephrocalcinosis by radiograph, ultra likely has a toxic nodule or nodules as the cause for her mild
sound, or CT) is an indication for surgical treatment ofhyper hyperthyroidism. Since multiple nodules were identified on
parathyroidism in otherwise asymptomatic patients. Other ultrasound, it is important to ascertain which of the nodules
indications for surgery in asymptomatic patients include age are autonomous, as the likelihood of malignancy in such
younger than 50 years; a serum calcium level greater than lesions is very low. Performing a thyroid scan will help iden
or equal to 1 mg/dL (0.25 mmol/L) above upper limit of nor tify whether one or more of the nodules is responsible for her
mal; a T-score of -2.5 or worse at the lumbar spine, total hip, thyroid function abnormalities.
femoral neck, or distal radius: or in those in whom medical A thyroid scan will also determine if fine-needle aspi
surveillance is neither desired nor possible. Patients with ration is indicated elsewhere in the gland. Nodules identi
these indications are considered to have the highest potential fied as autonomously functioning (or "hot") do not require
benefit from surgery. fine-needle aspiration, whereas nodules that are either "cold"
104
Answers and Critiques
or "warm" (of similar uptake to the surrounding non-nodular specific kind of radiation therapy) would be considered in
thyroid tissue) may require cytologic evaluation. a patient with a tumor that is refractory to medical therapy
This patient may ultimately benefit from methimazole and incompletely resectable.
therapy, but since her hyperthyroidism is mild, it is safe to Because this patient has a prolactinorna, the treatment
wait to initiate medical therapy until after the thyroid scan of choice is a dopamine agonist, not surgery. There is an
is performed . In patients with a greater degree of thyrotoxi excellent chance that the prolactinoma will respond to cab
cosis, beginning methimazole to lower the thyroid hormone ergoline, and the patient can avoid surgery.
levels prior to performing additional testing is reasonable.
KEY POINT
Once the hormone levels are nearing the normal range,
the thionamide should be withheld for s days prior to the • Dopamine agonists, such as cabergoline, are first-line
thyroid scan. therapy for symptomatic patients with prolactinomas.
If the patient is found to have a toxic nodule or multiple
toxic nodules, surgical removal is a reasonable treatment Bibliography
approach, particularly if there are compressive symptoms Melmed S. Casanueva FF, Hoffman AR. et al. Diagnosis and treatment of
hyperprolactinemia: An Endocrine Society clinical practice guideline. J
from the goiter. Since this is considered an elective proce Clin Enclocrinol Metab. 2011 Feb:96(2):273-88. [PMID: 21296991]
dure, administering low-dose methimazole to normalize
of her thyroid hormone levels would be advisable prior to
Cl
surgery.
Item 20 Answer: B
KEY POINT Educational Objective: Diagnose hypoglycemia in a
• Performing a radioactive iodine (123 1) thyroid uptake patient with diabetes mellitus taking a sulfonylurea.
and scan is the most appropriate initial management Hypoglycemia is the most likely cause of this patient's
for a patient who has mild hyperthyroidism most altered mental status. In patients taking a sulfonylurea for
likely caused by a toxic nodule or nodules. diabetes who develop dehydration, such as this patient with
decreased oral intake in conjunction with nausea and vom
Bibliography iting. impaired kidney perfusion may lead to altered phar
Jameson JL. Minimizing unnecessary surgery for thyroid nodules. N Engl J macokinetics and an increased risk of hypoglycemia related
Med. 2012 Aug 23:367(8):765-7. [PMID: 227316711
to ongoing effects of the medication and minimal carbo
hydrate intake. Although sulfonylureas are very effective
Item 19 Answer: A antihyperglycemic medications. most agents have relatively
long half-lives. allowing convenient daily dosing. However,
Educational Objective: Treat a macroprolactinoma.
this slower clearance predisposes to hypoglycemia com
The patient has a macroprolactinoma, which is best treated pared with other antiglycemic medications, particularly
with a dopamine agonist such as cabergoline. The most com when kidney function is impaired. Glyburide, in particular.
mon cause of hyperprolactinemia is a prolactinoma, which is has a longer half-life than olher sulfonylureas and its use is
a benign adenoma. Microprolactinomas are less than 10 mm recommended against in older patients by the Beers Crite
in diameter, and macroprolactinomas are 10 mm or greater ria. a list of medications that should be avoided or used with
in diameter. Prolactinomas are the most common type of caution in older pal ients. Although she last took glimepiride
secretory pituitary adenoma. The patient's tumor is causing more Lhan 24 hours before her presentation with altered
significant mass effect, including compression of the optic mental status. she was dehydrated. thus prolonging the
chiasm, invasion into the cavernous sinus, secondary hypo glucose-lowering effects or this insulin secretagogue for
thyroidism, and likely growth hormone deficiency; however, several clays.
even with these complications, the macroprolactinoma is Although patients with diabetes are at increased risk
best treated with medication instead of surgery. A dopamine for atherosclerolic cardiovascular disease. this patient does
agonist can cause a rapid decrease in the serum prolactin not have local abnormalities suggesting a cerebrovascular
level and shrinkage of the prolactinoma. More specifically, in accident. and stroke itself' is nol a common cause of isolated
as many as 90% of patients, it can normalize prolactin levels, altered mental status.
reverse hypogonadism, and shrink tumors by at least 50%. Levothyroxine also has a relatively long half-life allow
Because of these rapid decreases in tumor size, dopamine ing once daily dosing in most patients. Missing one or sev
agonists can be used as first-line therapy, even in patients eral closes of levothyroxine would therefore not likely lead
with mild visual field defects, as long as visual acuity is not to a degree of hypothyroidism causing acute mental status
threatened by rapid progression of the h1mor or recent tumor changes.
hemorrhage. Statin toxicity is unusual. and the most common toxic
Octreotide is used to treat acromegaly but has no role in ity associated with statin use is musculoskeletal symptoms.
the first-line treatment of prolactinoma. Increased stat in levels are not typically associated with men
Medical therapy is preferred over surgery and radiation tal status changes and would likely not be the cause of this
for the treatment of prolactinomas. Stereotactic surgery (a patient's menLal status changes.
105
Answers and Critiques
106
Answers and Critiques
CJ Item 24
ciated with nonmodifiable risk factors such as age, sex,
Answer: B menopausal status, height, and build, it is always important
to assess for possible secondary causes of bone loss that
Educational Objective: Treat a patient with diabetic
might be amenable to treatment, particularly if there is clin
ketoacidosis.
ical suspicion in a specific patient. Appropriate laboratory
This patient has diabetic ketoacidosis (OKA) and a low serum testing for most patients with newly diagnosed osteoporosis
potassium level, so potassium chloride should be adminis includes complete blood count (for malignancy), complete
tered. The patient should be making adequate urine before metabolic profile (for calcium levels and kidney function),
adminjstration of potassium replacement. Low potassium TSH, 25-hydroxyvitamin D, and urine calcium (screening for
stores in the body will need correction prior to initiation hypercalciuria), most of which were normal in this patient.
of insulin therapy to avoid cardiac arrhythmias. Potassium However, this patient's history of unintentional weight loss
chloride should be added to each liter of intravenous fluids to over the past year may be her only symptom of hyperthy
maintain the serum potassium level in the 4.0 to 5.0 mEq/L roidism, which could be contributing to her osteoporosis
(4.0-5.0 mmol/L) range with the continued use of intrave and would be important to treat in addition to therapy
nous insulin tl1erapy. directed toward her osteoporosis. Therefore, measuring this
Antibiotic therapy is not warranted at this time. The patient's TSH level would be appropriate prior to starting
mild leukocytosis upon presentation is most likely related to therapy for osteoporosis.
stress from OKA rather than an infectious process. ln addi Both serum and urine markers of bone turnover mea
tion. the chest radiograph is normal. sure collagen breakdown products and other chemicals
Sodium bicarbonate provides no added benefit when released from osteoclasts and osteoblasts as part of bone
the arterial blood pH is greater than 6. 9 and may be asso metabolism. However, they are not commonly used in most
ciated with harm. A 2011 systematic review found that patients with osteoporosis primarily because there is signif
bicarbonate administration worsened ketonemia. Several icant variability in the different measures in an individual
studies found higher potassium requirements in patients patient or between different patients, making standard
receiving bicarbonate. Studies in children found a possi ization of results difficult. Therefore, their use is typically
ble association between bicarbonate therapy and cerebral limited to research settings or in management of specific
edema. patients who have failed to respond to usual therapy for
During the treatment of OKA, initiation of insulin osteoporosis.
therapy and correction of acidosis will shift the extracel There is evidence that estrogen is effective for preven
lular potassium back into the intracellular space. Signifi tion and possibly treatment for osteoporosis, although the
cant worsening of the hypokalemia noted at presentation significant nonskeletal risks associated with this therapy
could occur if this is not corrected to a serum potassium have led to its not being used in favor of bisphosphonates.
level higher than 3.3 rnEq/L (3.3 mrnol/L) prior to initi As this patient is postmenopausal and has no clinical sug
ation of insulin therapy, which could lead to the devel gestion of excess estradiol secretion, and bisphosphonate
opment of arrhythmias. Insulin therapy can be safely therapy would be considered preferable to estrogen despite
initiated once the serum potassium level is greater than serum levels, testing for estradiol would not be indicated in
3.3 mEq/L (3.3 mmol/L). this patient.
107
Answers and Critiques
108
Answers and Critiques
c::J
disease course without evidence of microvascular dis
Item 28 Answer: D ease. For other wise healthy adults meeting these criteria,
Educational Objective: Diagnose hypomagnesemia the American Diabetes Association recommends a hemo
as a cause of hypocalcemia. globin A 1c level of less than 7.0%, preprandial glucose
values of 70 to 130 mg/dL (3.9-7.2 mmol/L), and 1- to
This patient's magnesium level should be checked. He has a 2-hour postprandial glucose values of less than 180 mg/dL
very low calcium level that is likely contributing to his clinical (10 mmol/L). Because the patient has not met these goals,
findings of tremulousness, muscle irritability, and electro a pharmacologic agent should be added at this time. Life
cardiogram changes. 1-le struggles with alcohol abuse, and style recommendations consisting of increased physical
his low albumin level suggests malnutrition. likely due to his activity, dietary modifications, and weight loss (if BMI is
chronic alcohol intake as a primary source of calories. Mag elevated) are the initial first step in treating diabetes. When
nesium deficiency is common in persons who abuse alcohol. lifestyle modifications fail to meet glycemic goals within
Furthermore, he has had diarrhea for several days, which will 6 weeks, metformin is the recommended first-line ther
also deplete his magnesium stores. Th.is patient's low calcium apy to be started in conjunction with continued lifestyle
level should promote parathyroid hormone (PIH) secretion modifications. If glycemic goals are not met after 3 months
to help correct the hypocalcemia. However, decreased levels of lifestyle modifications and metformin use, additional
of magnesium impair release of PIH; levels in patients with agents should be added to the regimen every 3 months
significant magnesium deficiency are either low or inappro until glucose goals are met.
priately in the normal range. Low magnesium levels are also Dapagliflozin, a sodium-glucose transporter-2 (SGLI-
associated with resistance to PIH activity at the level of bone. 2) inhibitor, increases excretion of glucose through the
further contributing to hypocalcemia. ·n1erefore, in patients kidney. It is a second-line agent that should be used after
with hypocalcemia and hypomagnesemia. it is crucial to cor lifestyle modifications and metformin fail to reach glyce
rect the magnesium level (to at least 2 mg/c!L [0.83 mmol/L]), mic goals.
as it is clifficult to increase calcium levels until this is done. The sulfonylurea glipizide stimulates insulin secretion
1,25-Dihydroxyvitamin D has a short half-life, and from the pancreatic beta cells. This agent could improve
its measurement only reflects the active levels of vitamin the patient's postprandial hyperglycemia, but it may also
D. Since active levels tend to vacillate frequently based on induce weight gain in a patient actively working on weight
immediate need, this level would not be diagnostically help loss. Glipizide is a second-line agent that should be used
ful. 25-Hydroxyvitamin D levels have a longer half-life and. after lifestyle modifications and metformin fail to reach
therefore. more accurately reflect the total body stores of glycemic goals.
vitamin D. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhib
Measuring 24-hour urine calcium excretion in this itor, improves glycemic control by slowing gastric emp
patient would not be diagnostically helpful as significant tying and suppressing glucagon secretion. It is also con
urinary loss of calcium is uncommon, and the urine calcium sidered a second-line agent that might be considered if
level in this patient would be expected to be low due to com lifestyle modifications and metformin fail to reach glyce
pensatory kidney retention of calcium. mic goals.
Checking the ionized calcium level is inclicated in settings
KEY POINT
where abnormal serum protein binding of calcium is possible.
TI1is test is not needed in this symptomatic patient who has no • For most patients with type 2 diabetes mellitus, life
suggestion of excessive protein binding of calcium. style modifications and metformin therapy are the
most appropriate initial treatments.
KEY POINT
109
Answers and Critiques
110
Answers and Critiques
111
Answers and Critiques
form, 1.25- dihydroxyvitamin D (calcitriol), is lost, as is the rapid-acting insulin, before intensive exercise. Since the dura
signal to increase reabsorption of calcium in the kidney in the tion of action of insulin glulisine can extend up to 4 hours, cov
distal convoluted tubule and loop of Henle. As a result, both ering the meal consumption prior to exercise with a smaller
calcitriol and calcium supplementation must be provicl�d. dose of insulin glulisine can reduce the risk of hypoglycemia
as was done in this patient. However, without reabsorption in the setting of intense or prolonged exercise.
of calcium by the kidney, oral calcium will be absorbed and Discontinuation of insulin glargine in a patient with
passed through the kidney, resulting in higher levels of urine type 1 diabetes will lead to hyperglycemia if the rapid-acting
calcium than in patients with normal parathyroid hormone insulin isn't adjusted to provide basal insulin coverage. The
levels. In monitoring calcium status in hypoparathyroid hyperglycemia and insulin deficiency that develop in the
patients, the recommended goal should be a 24-hour urine absence of basal insulin coupled with the stress associated
calcium level of less than 300 mg/24 hours (7.5 mmol/24 h) with exercise will lead to an increase in the release of coun
with a concomitant serum calcium level in the low normal terregulatory hormones. In this scenario, there may not
range (8.0-8.5 mg/dL [2.0-2.l mmol!L]). lf the urine calcium be sufficient insulin to decrease lipolysis and subsequent
levels are surpassed, it is appropriate to decrease the calcium oxidation of free fatty acids. This could lead to diabetic
intake first; in patients with serum calcium levels greater ketoacidosis.
than 8.5 mg/dL (2.1 mmol!L) and urine calcium greater than The meal-time insulin prior to exercise should be
300 mg/24 hours (7.5 mmol/24 h), concurrent decreases in decreased; however, modification of the diet with increase
both calcium supplementation and calcitriol are indicated. in carbohydrates, rather than protein, can also help avoid
Although 25-hydroxyvitamin D levels are the best indi exercise-induced hypoglycemia. Consumption of 15 to 30
cator of total body vitamin D stores in patients with normal grams of carbohydrates prior to exercise and/or a snack with
parathyroid function, it would not be helpful for therapeutic complex carbohydrates after prolonged exercise can help
decision-making in this patient as the lack of PTH requires mitigate the risk of hypoglycemia. Carbohydrates, especially
treatment with activated (1,25-dihydroxy) vitamin D. In this simple ones, can rapidly provide glucose to the bloodstream
patient, 1,25-dihydroxyvitarnin D levels measured concur and maximize glycogen stores in the liver that can be utilized
rently with the serum and urine calcium levels are the most for fuel during exercise. The digestion time for protein is
appropriate indicators of therapeutic effect. prolonged compared with carbohydrates, thus providing a
Removal of the parathyroid glands does not allow the slower source of energy during exercise
PTH level to be used to monitor appropriateness of therapy. A sliding-scale regimen of insulin glulisine is a reactive
It would be expected to be low or undetectable in this patient management plan for glucose control. In this scenario, it
who has had resection of his parathyroid glands and chemo is possible that the patient could have an increased risk of
therapy and radiation. hyperglycemia or hypoglycemia prior to, during, or after
It would be inappropriate to continue the current exercise secondary to insufficient or excessive doses of insu
regimen given the elevated 24-hour urine calcium levels. lin from the sliding-scale regimen.
Persistently elevated levels could lead to nephrolithiasis or
KEY POINT
nephrocalcinosis.
• Because exercise can increase glucose utilization by
KEY POINT
the muscles, reducing the doses of mealtime insulin in
• The urine and serum calcium goals are different in a patient with diabetes mellitus will decrease the risk
patients with hypoparathyroidism; the urine calcium of hypoglycemia with intense or prolonged exercise.
goal is less than 300 mg/24 hours (7.5 mmol/24 h)
and serum calcium goal is between 8.0 and 8.5 rng/dL Bibliography
(2-2.1 mmol!L) in these patients. American Diabetes Association. (4) Foundations of care: education. nutri
tion. physical activity, smoking cessation. psychosocial care. and immu
nization. In: Standards of Medical Care in Diabetes-2015. Diabetes Care.
Bibliography 2015 Jan:38 Suppl l:S20-30. [PMID: 25537702]
Khan MS. Waguespack SG. Hu M. Medical management of postsurgical
hypoparathyroidism. Endocr Pract. 2011 Mar-Apr:17 Suppl 1:18-25.
[PMID: 21134871]
Item 36 Answer: A
Educational Objective: Diagnose central
Item 35 Answer: A hypothyroidism.
Educational Objective: Manage exercise-induced
hypoglycemia.
Measurement of the serum free thyroxine (T) level is the
most appropriate next step in management for this patient
This patient should decrease his meal-time insulin glulisine who has clinical evidence of hypothyroidism (fatigue, con
dose prior to exercise and continue his insulin glargine. Exer stipation, cold intolerance, dry skin, delayed reflexes, ane
cise can increase glucose utilization by the muscles, which can mia, and mild hyponatrernia) but has had radiation to the
induce hypoglycemia in the setting of exogenous insulin. This base of the skull, including the pituitary gland. Although
patient consumes a meal and administers insulin glulisine, a measurement of thyroid-stimulating hormone (TSH) is the
112
Answers and Critiques
most accurate reflection of thyroid status in patients with an rarely associated with hypercalcemia and therefore does not
intact hypothalamic-pituitary-thyroid axis, it is not a reliable require therapy to lower serum calcium levels. Screening
measure of thyroid function in patients in whom there is other family members for the disorder is indicated.
loss of hypothalamic-pituitary function, such as seen in this Bone densitometry is not indicated in this age group in
patient. His low-normal TSH in the context of clinical hypo the absence of fragility fractures or other risk factors such as
thyroidism suggests possible central hypothyroidism, and long-term high-dose glucocorticoid use or primary hyper
measurement of the circulating level of thyroid hormone, the parathyroidism.
free serum T 4, would therefore be a more accurate indication A parathyroid sestamibi scan is a very useful nuclear
of his thyroid status. imaging study for localization of adenomas in patients with
Repeating the TSH measurement would not be appro primary hyperparathyroidism or parathyroid cancer. How
priate in this patient with signs and symptoms of hypothy ever, primary hyperparathyroidism has not been confirmed
roidism, as untreated hypothyroidism leads to increased in this patient with suspicion for FHH, making this study
cardiovascular morbidity and mortality. In addition, because premature.
of likely central hypothyroidism, the TSH level would remain The need for surgical treatment in this patient has also
an inaccurate indicator of thyroid function. not been established. Therefore, surgical referral for parathy
Thyroid scintigraphy is unlikely to distinguish the roidectomy would not be appropriate.
source of the hypothyroidism, as patients with primary
KEY POINT
or secondary hypothyroidism have decreased radioactive
uptake. Thyroid scanning is most helpful in elucidating the • Measurement of 24-hour urine calcium and
cause of hyperthyroidism. creatinine levels will distinguish between primary
Ultrasound of the neck is normal in patients with cen hyperparathyroidism and familial hypocalciuric
tral hyperthyroidism and would be unlikely to provide any hypercalcemia.
additional information about this patient's thyroid status.
Bibliography
KEY POINT
Shinall MC Jr, Dahir KM, Broome JT. Differentiating familial hypocalciuric
• When central hypothyroidism is suspected, measure hypercalcemia from primary hyperparathyroidism. Endocr Pract. 2013
Jul-Aug;l9(4):697-702. [PMID: 234256441
ment of the serum free thyroxine (T 4) level is essential.
Bibliography
Item 38 Answer: D
Persani L. Clinical review: Central hypothyroidism: pathogenic, diagnostic,
and therapeutic challenges. J Clin Endocrinol Metab. 2012Sep;97(9):3068- Educational Objective: Evaluate timing of prandial
78. [PMID: 22851492]
insulin in a patient with diabetes mellitus.
113
Answers and Critiques
digestive system. However, the lack of gastrointestinal symp Postoperative norepinephrine is not inclicatecl. If the
toms, absence of clinical evidence of other diabetes-related patient were to experience hypotension or shock postop
complications, and her hemoglobin A 1c history suggesting eratively. treatment with vasopressors in addition to gluco
good diabetic control make gastroparesis a less likely cause corticoid replacement would be considered: however. this
of her erratic blood glucose readings. would not replace the administration of' glucocorticoids in
Inadequate insulin dosing can cause fluctuations in gly this population at risk for acute hypocortisolism.
cemic control. However, this patient reports little variability Preoperative phenoxybenzamine is indicated in the
in her daily diet. She also has several days with evidence of management of patients with pheochromocytoma. not CS.
adequate glycemic control on her current insulin regimen The purpose of preoperative ex-blockade is to provide blood
doses. Therefore, inadequate dosing is less likely to be the pressure control and decrease the risk of cardiovascular
cause of her glycemic variability. complications related to excessive catecholamine release
during intraoperative manipulation or the tumor.
KEY POINT
KEY POINT
• Because meal coverage with insulin should mimic the
physiologic pattern seen with endogenous insulin • Following adrenalectomy, patients with adrenal
secreted from the pancreatic beta cells as closely as Cushing syndrome should be treated with stress-dose
possible, insulin administration in patients with dia glucocorticoids during the postoperative period to
betes mellitus should ideally occur prior to or at the avoid the risk of acute hypocortisolism.
time of the meal consumption.
Bibliography
Bibliography Di Dalmazi G, Berr CM, Fassnacht M. el al. Adrenal function after adrenal
ectomy for subclinical hypercortisolism and Cushing's syndrome: A
DeWitt DE, Hirsch 18. Outpatient insulin therapy in type 1 and type 2 diabe systematic review of the literature. JCEM. 2014;99:2637-2645. [PMID:
tes mellitus. JAMA. 2003 May 7:289(17):2254-64. [PMID: 12734137] 24878052]
CJ Item 39 Answer: A
Educational Objective: Manage a patient with
Item 40 Answer: A
Educational Objective: Manage Paget disease of bone.
Cushing syndrome following adrenalectomy.
Initiating antiresorptive therapy in this patient with symp
The most appropriate management of this patient under tomatic Paget disease of bone is the most appropriate next step
going right adrenalectomy for Cushing syndrome (CS) in management. Paget disease of bone is characterized by focal
is postoperative hydrocortisone. The patient has adre areas of accelerated bone remodeling that ultimately causes
nocorticotropic hormone ( ACTH)-independent CS. and overgrowth of bone at one or more sites that may impair the
a contrnst-enhanced adrenal CT scan demonstrated a integrity of affected bone. Areas commonly affected include
right adrenal mass with imaging characteristics consis the skull, spine, pelvis, and long bones of the lower extrem
tent with a benign adenoma. Adrenocortical adenomas ities, such as in this patient who has thickened cortical bone
typically have low attenuation on unenhanced CT scan and coarsening of the trabecular bone of the femur. The main
(density Jess than 10 Hounsfield units) and exhibit rapid indications for antiresorptive therapy in most patients include
washout of intravenous iodine contrast media (>50% pain caused by increased bone metabolic activity (as in this
at LO minutes). Following adrenalectomy. patients with patient) and hypercalcemia due to multiple affected sites. The
adrenal CS may develop acute adrenal railure because 01· most commonly used treatment agents are nitrogen-contain
hypothalamic-pituitary-adrenal (I-IPA) axis suppression ing bisphosphonates (alendronate, pamidronate, risedronate,
and contralateral adrenal atrophy. All patients should be and zoledronic acid); these are the newer bisphosphonates
treated with stress-dose glucocorticoids and tapered to and have been the most extensively studied for treatment of
physiologic replacement until HPA axis recovery is con Paget disease of bone. Bisphosphonates stabilize bone turn
l'irmed. Most patients have adrenal insufficiency lasting over by suppressing bone resorption and new bone forn1ation
as long as l2 months. with a resulting reduction in serum alkaline phosphatase
Postoperative administration or mitotane. an adreno levels. There is no evidence that antiresorptive therapy is ben
lytic drug. is recommended as acljuvant therapy for patients eficial in asymptomatic patients.
with locally persistent or metastatic adrenocortical carci Bone biopsy is rarely needed to establish the diagnosis
noma (ACC). In these patients. mitotane is associated with of Paget disease of bone when there are characteristic radio
objective remissions in approximately 25% of patients. ll1is graphic findings of bone turnover (concurrent osteolytic and
patient's CT scan findings are not consistent with ACC. Adre osteoblastic changes) and consistent laboratory studies (such
nal cancers are typically large (>4-6 cm) with irregular mar as elevated serum alkaline phosphatase levels). Bone biopsy
gins and areas of necrosis or calcification. Unenhanced CT may be useful in certain situations in which bone lesions are
will demonstrate high attenuation (density >LO Hounsfleld primarily osteoblastic (suggesting possible metastatic dis
units). and washout of intravenous iodine contrast media is ease) or osteolytic (possibly indicating multiple myeloma),
less than 50% at 10 minutes. neither of which are present in this patient.
114
Answers and Critiques
The bone lesions of multiple myeloma are primarily proteins. The increased thyroid hormone requirements of the
osteolytic, in which case further evaluation for that diagnosis fetus also contribute to this change in serum T4 levels.
with a serum and urine protein electrophoresis would be In this patient, with a serum TSH value above 2.5 µU/mL
appropriate. However, this patient's radiographic findings (2.5 mU/L) during the first trimester, the dose of levothyrox
are not consistent with a diagnosis of multiple myeloma, ine needs to be increased rather than decreased or discon
and further evaluation for this disorder would therefore not tinued. The serum TSH level should be rechecked in 4 weeks
be indicated. to ensure that the dose adjustment continues to be adequate.
Most patients with Paget disease of bone are asymp Likewise, thyroid function tests should be repeated at least
tomatic and are identified only by elevated serum alkaline once during each trimester to ensure that additional adjust
phosphatase levels detected on laboratory studies obtained ments in the levothyroxine dose are not needed.
for other reasons. In many patients with mild disease, clini
KEY POINT
cal observation without initiation of therapy is appropriate.
However, in this patient with symptomatic disease in a • On confirmation of pregnancy in a patient taking lev
critical weight-bearing skeletal area, clinical observation othyroxine, serum thyroid-stimulating hormone
without treatment would not be appropriate. should be checked to determine the need for levothy
roxine dose adjustment.
KEY POINT
Item 41 Answer: D ll1is patient most likely has primary adrenal failure due to
bilateral adrenal hemorrhage. I-le has acute onset nausea.
Educational Objective: Treat hypothyroidism in
lightheadedness. back and abdominal pain. and hypoten
pregnancy.
sion. While nonspecific. these findings are consistent with
This pregnant patient's levothyroxine dose should be adrenal failure. Additionally. laboratory studies show hypo
increased to lower the serum thyroid-stimulating hormone. natremia, hyperkalemia. and hypocortisolemia. which are
Maternal thyroid hormone production typically increases by also consistent with the diagnosis. A sudden drop in the
30% to 50% during pregnancy; therefore, in pregnant patients hemoglobin c1nci hematocrit. as seen in this patient, may be
requiring levothyroxine supplementation, the replacement present without evidence of' bleeding elsewhere. Risk fac
dose usually needs to be increased to provide adequate thy tors for adrenal hemorrhage include anticoagulant therapy
roxine (T4) for the neurologic development of the fetus. The (and may occur with treat mcnt levels within the therapeutic
combination of this patient's elevated thyroid-stimulating range), the postoperative slate. abnormalities of hemostasis
hormone (TSH) level and low total T,1 level suggest that her (such as heparin induced thrombocytopenia or antiphos
levothyroxine dose should be increased. During pregnancy, pholipid antibody syndrome). and sepsis. Because adrenal
the physiologic changes in thyroid hormone levels include a hemorrhage is uncommon and the associated f·indings may
reduction in the serum TSH level and an increase in the serum be relatively nonspecific. an increased level of' suspicion is
total T,1 level. This change in the serum TSH level is partly required for the diagnosis in at-risk patients: failure to iden
due to the rise in the serum human chorionic gonadotropin tify acute adrenal failure in a timely manner may lead to car
(HCG) level; both hormones share sequence homology in diovascular collapse. Adrenal hemorrhage can often be visu
their a subunit. As the serum HCG level rises with progression alized on abdominal er imaging. Treatment of'acute adrenal
of pregnancy, the hormone can bind to the TSH receptors, failure is with stress-close glucocorticoicis (hydrocortisone.
resulting in a reduction in serum TSH levels. Consequently, 50-100 mg intravenously every 6-8 hours) and supportive
the normal reference range for serum TSH during pregnancy care with intravenous fluids and vasopressors as needed for
shifts to a lower value. from 0.5 to 5.0 µU/mL (0.5-5.0 mU/L} hcmoc\ynD 111 ic compromise.
pre-pregnancy to 0.03 to 2.5 µU/mL (0.03-2.S mU/L) during Although autoimmune adrenalitis may cause primary
the first trimester. Additionally, the serum total T4 level rises ,idrenal failure and is associated with the presence of' other
LS-fold above the normal nonpregnant reference range. Part autoi mmune diseases (such as hypothyroiclism in this
of this increase is due to the higher levels of estrogen associ patient). the onset of' sy mptoms related to hypocortisolism
ated with pregnancy, which cause an increase in serum total are usually more gradual. and skin hyperpigmentalion is
protein levels, including serum thyroid hormone-binding often seen on examination.
115
Answers and Critiques
Cl
CONT.
Chronic ad 111 in isl rat ion of long-acting opiate medica
tions is a known cause or hypogonadotropic hypogonad
Measuring 24-hour urine free catecholamine and meta
nephrine levels would be used to screen for pheochromo
ism and a potential etiology or secondary adrenal insuffi cytoma. If this patient had an adrenal adenoma, she would
ciency. ·111e aclrninistrat ion or relatively short-acting opiates certainly need to be screened for pheochromocytoma prior
(oxycoclone) on an as-neeclcd basis for postoperative pain to surgery, but she does not have a known adrenal lesion. Her
is unlikely to cause clinically significant hypothalamic symptoms and comorbidities are explained by her diagnosis
pituitary adrenal axis disturbance. Hypogonaclotropic of Cushing disease, and she has no specific signs or symp
hypogonaclisrn would also not present with hyperkalemia toms that require an evaluation for pheochromocytoma.
because rnineralocorticoid secretion is preserved. A PET scan is not necessary or indicated in the evalu
Pituitary apoplexy results from acute hemorrhage ation of Cushing syndrome. Cushing disease is caused by a
into the pituitary and may result in adrenal insufficiency. pituitary adenoma and is not malignant. Cushing syndrome
Although this patient might be at increased risk clue to due to ectopic ACTH production is often caused by a can
anticoagulation. he does not have headache or visual distur cer. PET scan may be indicated to try to localize the source
bances, which arc common in pituitary apoplexy. Because of ectopic ACTH, but the source of the excessive ACTH is
pituitary apoplexy causes secondary adrenal insufficiency. it already known to be from a pituitary adenoma.
would not result in hyperkalemia.
KEY POINT
KEY POINT • Patients with hypercortisolism should have a screen
• Patients with bilateral adrenal hemorrhage typically ing dual-energy x-ray absorptiometry scan because
present with clinical features of acute cortisol and they are at a high risk of osteoporosis and fracture.
aldosterone deficiency, including gastrointestinal dis
turbance, lethargy, weakness, hypotension, shock, Bibliography
hypoglycemia, and electrolyte imbalances, such as Nieman LK. Biller BMK. Findling JW, et al. The diagnosis of Cushing's syn
drome: an Endocrine Society clinical practice guideline. J Clin Endocrinol
hyponatremia and hyperkalemia. Metab. 2008 May;93(5):l526-40. [PMID: 18334580]
Bibliography
Cl
Rosenberger LH. Smith PW, Sawyer RG, et al. Bilateral adrenal hemorrhage:
the unrecognized cause ofhemodynamic collapse associated with hepa
Item 44 Answer: D
rin-induced thrombocytopenia. Crit Care Med. 2011 Apr;39(4):833-8 Educational Objective: Manage primary adrenal failure.
[PMID: 21242799]
1 he most appropriate regimen for the long-term treatment of
this patient's primary adrenal failure would be preclnisone,
Item 43 Answer: C 5 mg once daily, and fluclrocortisone, 0.05 mg once daily. In
prima1y adrenal failure, there is a failure in the production
Educational Objective: Evaluate a patient with a new
or all the hormones or the adrenal cortex. Patients therefore
diagnosis of hypercortisolism for osteoporosis.
require both glucocorticoicl and mineralocorticoicl replace
1l1is patient with newly diagnosed hypercortisolism is at ment. Because she is no longer ill, physiologic replacement
high risk for osteoporosis and fracture, and a screening dual doses are appropriate. Prcdnisone primarily has glucocor
energy x-ray absorptiometry (DEXA) scan is indicated. 1l1e ticoid activity. with 5 mg being consiclerecl a physiologic
mechanism of osteoporosis in patients with Cushing syn replacement dose. It is also long-acting so may be adminis
drome is related to decreased intestinal calcium absorp tered once daily in combination with fludrocortisone. which
tion, decreased bone formation, increased bone resorption, has almost pure mineralocorticoicl properties. Physiologic
and decreased renal calcium reabsorption. Patients with low replacement closes or fludrocortisone are 0.05 to 2 mg per clay.
bone density should be considered for bisphosphonate treat Dexamethasone is primarily a glucocorticoid and
ment to reduce the risk of fracture. could be used as the glucocorticoicl portion or combination
An 8-mg dexamethasone suppression test can be used replacement therapy with a mineralocorticoid such as flucl
to help localize the source of adrenocorticotropic hormone rocortisone. However, dexamethasone alone would not be
(ACTH) in a patient with Cushing syndrome. Patients with appropriate therapy for primary adrenal failure due to its
pituitary Cushing disease respond to 8 mg of dexamethasone intrinsic lack ofmineralocorticoicl activity.
with a suppressed cortisol level. In comparison, patients Fluclrocortisone alone is also inappropriate because it
with ectopic ACTH production do not respond to 8 mg of would not provide glucocorticoid replacement.
dexamethasone, and their cortisol levels remain elevated. Hydrocortisone has both glucocorticoid and mineralo
However, this test is associated with a number of false corticoicl properties. with primarily glucocorticoid activity
positive results. The 8-mg dexamethasone suppression test is at physiologic replacement doses of 12.5 to 25 mg in two to
not indicated for this patient because she has already had a three divided doses daily. At total daily doses above 50 mg.
more definitive test. Intrapetrosal sinus sampling has better hyclrocortisone has adequate 111 ineralocort icoid activity to
sensitivity and specificity when completed by a skilled inter allow for its use as monotherapy. However, treatment with
ventional radiologist. hydrocortisone, 10 mg three times daily. does not provide
116
Answers and Critiques
Cl
CONT
adequate mineralocorlicoid replacement. while il supplies
a supraphysiologic amount ofglucocorticoid lh,1l could lead
CT are typically a patchy infiltrate with minimal lymphade
nopathy. This patient's image reveals marked diffuse enlarge
to iatrogenic Cushing syndrome if administered on a long ment of the thyroid, and she did not have a history of prior
term basis. illness.
Patients with primary adrenal failure require adclilional
KEY POINT
glucocorticoicl at times or physiologic stress. Treatment for
minor stress (upper respiratory infection, lever. minor sur • Primary thyroid lymphoma most often occurs in
gery under local anesthesia) is typically two to three limes elderly women with underlying hypothyroidism; the
the basal close of hyclrocortisone (or equivalent). for moder typical presentation includes rapidly enlarging goiter,
ate stress (minor or moderate surgery with general anesthe weight loss, and night sweats, and imaging reveals a
sia) usually 45 to 75 mg/clay, and major stress (major smgery, diffusely enlarged thyroid.
trauma , critical illness. or childbirth) up to 150 lo 200 mg/
day with a gradual taper following resolution or the stress. Bibliography
Kim HC. Han MH. Kim KH, et al. Primary thyroid lymphoma: CT findings.
KEY POINT Eur J Radial. 2003 Jun;46(3):233-9. [PMID: 127581171
• Patients with primary adrenal failure require both
glucocorticoid and mineralocorticoid replacement in
Item 46 Answer: E
physiologic doses.
Educational Objective: Treat primary hyperparathy
Bibliography roidism and concomitant vitamin D deficiency.
Neary N, Nieman L. Adrenal insufficiency: etiology, diagnosis and treatment. The most appropriate treatment of this patient is to replete
Curr Opin Endocrinol Diabetes Obes. 2010 Jun:17(3):217-23.(PMID:
20375886] his vitamin D deficiency with a supplement such as vitamin
D 3 (cholecalciferol). He has primary hyperparathyroidism as
shown by his elevated serum calcium and parathyroid hor
Item 45 Answer: C mone levels. However, there is a high prevalence of concurrent
vitamin D deficiency and insufficiency in patients with pri
Educational Objective: Diagnose primary thyroid
mary hyperparathyroidism, and low levels of 25-hydroxyvi
lymphoma.
tamin D can stimulate parathyroid hormone secretion in
The patient has primary thyroid lymphoma, which most often non-adenomatous glands. Because of this, measurement of
occurs in elderly women with a long-standing history of vitamin D levels should be ordered as part of the evaluation of
Hashimoto thyroiditis. The clinical presentation is typically primary hyperparathyroidism, and repletion should be pro
one of rapid onset (weeks) of an enlarging goiter with weight vided if identified. In these patients, it is in1portant to replace
loss and night sweats. The diagnosis is made by biopsy of the their vitamin D to a level of at least 30 ng/dL (75 nrnol/L).
thyroid with flow cytometry. Treatment typically involves After this level is reached, the patient should be placed on a
chemotherapy and/or radiation therapy. Thyroidectomy is vitamin D dosage to maintain that value. The choice to use
usually not needed. cholecalciferol versus ergocalciferol is often based on the level
CT scan of the neck, rather than ultrasound, was of vitamin D deficiency. Since ergocalciferol is more readily
ordered in this patient because of the compressive symp available in the 50,000 U form and has a shorter half-life, it
toms and positional breathing issues. CT scan allows visual is recommended when a patient's vitamin D level is less than
ization of the enlarged thyroid gland and assessment of the 10 ng/mL (25 nmol/L). Cholecalciferol is often used when
patency of the trachea. In this image, the "doughnut" sign the level is between 20 and 30 ng/mL (50-75 nmol/L) or for
can be seen, whereby the enlarged thyroid extends behind maintenance. Since this patient already has hypercalcemia
and completely encircles the trachea. and low-dose repletion is desired, the lower doses (400 U
New-onset Graves disease is unlikely to occur in a daily) of vitamin D3 (over-the-counter cholecalciferol) should
patient of this age, particularly with her long-standing his be used. This patient's serum calcium should be monitored at
tory of hypothyroidism. Furthermore, there is no bruit or least monthly.
other clinical sign of Graves disease, and the thyromegaly This patient does not meet the threshold for surgery. His
associated with Graves disease is not acute in onset. serum total calcium level is less than 1 standard deviation
This patient is unlikely to have papillary thyroid cancer, from upper limit of normal, his bone density score is not in
as these tumors typically grow very slowly, in contrast to the osteoporotic or treatment range, he is older than SO years
the acute onset of her findings. Additionally, the thy roid of age, and his glomerular filtration rate is preserved.
is not typically diffusely enlarged, as seen on this CT scan. Alendronate would be an excellent option for calcium
Rather, a distinct nodule and potentially concomitant cervi reduction and simultaneous treatment of osteoporosis if
cal lymphadenopathy would be expected. his T -scores were lower or Fracture Risk Assessment Tool
Subacute (de Quervain) thyroiditis is associated with (FRAX) scores were higher. The FRAX calculator defines the
acute onset of anterior neck pain. It is typically seen follow 10-year fracture risk for patients with T -scores in the - LO
ing a viral illness in the preceding months. The changes on to -2.S range. The FRAX calculator (www.shef.ac.uk/FRAX)
117
Answers and Critiques
incorporates multiple risk factors including sex, fracture organ function is stable and glucose levels have returned
history, femoral neck bone mineral density, steroid usage, to baseline values.
smoking, BM!, age, and alcohol intake to determine pro Sliding-scale insulin is nonphysiologic and can result
jected fracture risk. If the risk of major osteoporotic fracture in large fluctuations in blood glucose levels. Sliding-scale
is greater than or equal to 20% or the risk of hip fracture is insulin is not recommendecl as the sole insulin therapy in
greater than or equal to 3%, the patient's benefit from ther the hospital setting.
apy exceeds the risk and treatment should be offered.
KEY POINT
Calcitonin is an option for reducing his calcium levels,
but he is currently asymptomatic and does not warrant cal • For non-critically ill hospitalized patients with diabe
cium lowering. tes mellitus and hyperglycemia, a weight-based treat
Cinacalcet, a calcimimetic agent, is another option for ment plan that includes basal and prandial insulin is
lowering calcium for symptomatic patients with kidney recommended.
involvement. This patient has preserved kidney function
and no symptoms. Due to the cost and potential side effects Bibliography
of cinacalcet, it would not be indicated at this time. American Diabetes Association. (13) Diabetes care in the hospital, nursing
home, and skilled nursing facility. In: Standards of Medical Care in
KEY POINT Diabetes-2015. Diabetes Care. 2015 Jan:38 Suppl:S80-5. [PMID:
25537715]
• In patients with primary hyperparathyroidism and con
comitant vitamin D deficiency, 25-hydroxyvitamin D
levels should be repleted to at least 30 ng/dL (75 nmol/L)
Item 48 Answer: B
to prevent further parathyroid hormone stimulation.
Educational Objective: Diagnose Cushing syndrome.
Bibliography The most appropriate next diagnostic test for this patient is
Holick MF, Binkley N. Bischoff-Ferrari HA, Gordon C, Hanley D. Heaney R. the 1-mg dexamethasone suppression test. She has the typical
Weaver C. Evaluation, treatment and prevention of vitamin D deficiency :
a n Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. clinical features and findings of cortisol excess, or Cushing
2011 Jul;96(7):19ll-30. [PMlD: 21646368] syndrome. The most common cause of Cushing syndrome is
exogeneous glucocorticoid use; however, she has not received
glucocorticoids. To evaluate for Cushing syndrome, biochem
Item 47 Answer: A ical evidence of hypercortisolism must be confirmed by use
of several screening tests. Three screening tests are used for
Educational Objective: Manage diabetes mellitus in a
Cushing syndrome: the 1-mg dexamethasone suppression
hospitalized patient.
test (given late at night with assessment of cortisol suppres
The most appropriate treatment for this patient's diabetes sion the next morning), 24-hour urine free cortisol excretion
mellitus while hospitalized is a weight-based treatment (to quantify total daily cortisol secretion), and measurement
plan that includes basal and prandial insulin. Hypergly of evening salivary cortisol (which normally reaches a nadir
cemia in the hospital is associated with poor outcomes. at that time but remains elevated in patients with Cushing
According to the American Diabetes Association and syndrome). At least two abnormal first-line screening tests
American Association of Clinical Endocrinologists. glu are required for diagnosis. Only after establishing biochemical
cose goals in hospitalized patients in a non-ICU setting are hypercortisolism should the source of excess cortisol produc
premeal values less than 140 mg/ell (7.8 mmol/l) and ran tion be sought.
dom values less than 180 mg/ell (10 mmol/l). The Amer Measurement of adrenocorticotropic hormone (ACTH)
ican College or Physicians recommends avoiding values is not a screening test for Cushing syndrome. After docu
less than 140 mg/ell (7.8 mmol/L) to decrease the risk of mentation of excess cortisol production, ACTH levels may
hypoglycemic complications. The patient's plasma glucose be useful in determining if hypercortisolism is ACTH-de
values exceed the recommenclecl guidelines and require pendent or -independent; however, it is not an appropriate
treatment. initial screening test.
Oral agents clo not have safety or efficacy data for use An 8-mg dexamethasone suppression test is helpful in
in the J1ospital. Glipizide is an insulin secretagogue that can differentiating between Cushing disease (pituitary tumor
potentially induce hypoglycemia in the hospital setting. par secreting ACTH) and ectopic ACTH production. However,
ticularly with unpredictable changes in oral intake. it is not a screening test for Cushing syndrome and would
With rnetformin use, hospitalized patients can be appropriate only in specific situations after Cushing syn
develop poor organ perfusion. which can increase the drome is diagnosed.
risk of lactic acidosis. Intravenous contrast dye can also A pituitary MRI should be ordered only after hypercor
impair kidney function in the setting of metformin use in tisolism and Cushing syndrome are diagnosed and a pitu
the hospital. Reinitiation of the patient's home regimen itary adenoma is suspected as a cause.
or metformin at or near the time of discharge is most Measurement of serum cortisol levels lacks sensitivity
appropriate arter all procedures have been completed and and specificity for diagnosing Cushing syndrome, primarily
118
Answers and Critiques
due to the pulsatile nature of cortisol secretion, and is not Item 50 Answer: D
used as a screening test. Educational Objective: Diagnose an incidentally
KEY POINT noted adrenal mass.
• To screen for Cushing syndrome, biochemical evi 1l1e most appropriate next step in management is to evalu
dence of hypercortisolism must be confirmed by a ate for pheochromocytoma, preferably by measurement of
1-mg dexamethasone suppression test, 24-hour urine plasma free metanephrines in this patient. Approximately
free cortisol testing, and/or measurement of evening 10% to 15% of incidentally discovered adrenal masses are
salivary cortisol levels. functional, although most have no overt clinical manifesta
tions. Therefore, all patients with an incidentally noted adre
Bibliography nal mass should be evaluated for the autonomous secretion
Nieman LK, Biller BMK, Findling JW, el al. The diagnosis or· Cushing·s syn of cortisol and catecholamines, and those with hypertension
drome: An Endocrine Society clinical practice guideline. J Clin should also undergo testing for primary hyperaldosteronism.
Endocrinol Metab. 2008 May;93(5):l526-40. [PMID: 18334580]
The low-dose dexamethasone suppression test should be
performed to evaluate for subclinical Cushing syndrome
Item 49 Answer: A given its superior sensitivity compared with other screen
Educational Objective: Treat an obese patient with ing tests (24-hour urine free cortisol and late-night salivary
type 2 diabetes mellitus with bariatric surgery.
co11isol); this test was negative in this patient. Measurement
of 24-hour urine metanephrines and catecholamines is the
Patients with a BM! between 35 and 40 with one or more usual first test in most asymptomatic patients to evaluate
complications associated with obesity should be con for catecholamine hypersecretion, although in those with
sidered for bariatric surgery, with the goal of significant imaging suggestive of pheochromocytoma, measurement of
weight loss and improvement in metabolic abnormali plasma free metanephrines is the preferred study because of
ties. This obese patient has type 2 diabetes mellitus with its very high sensitivity and high negative predictive value for
advanced microvascular disease along with other compli a normal study. Imaging in this patient reveals a well-circum
cations associated with obesity including hypertension, scribed partially cystic lesion with high attenuation on non
hyperlipidemia, obstructive sleep apnea, gastroesophageal contrast CT scan, which is in keeping with a pheochromocy
acid reflux disease, and osteoarthritis. His attempts at life toma and is not typical of an adrenocortical adenoma, which
style management with diet and exercise did not result characteristically has low attenuation on CT scan (density <10
in weight loss that substantially improved his metabolic Hounsfield units) due to relatively high lipid content.
abnormalities or obesity. Management of an adrenal incidentaloma depends
Increasing the insulin doses could potentially exac on its size, imaging characteristics (phenotype), and hor
erbate the weekly hypoglycemic events occurring in a monal functioning. Almost all adrenal tumors that are
patient with hypoglycemic unawareness. 1l1is could also overtly functional are larger than 6 cm in size or have unfa
lead to more weight gain due to frequent treatments of vorable imaging characteristics should be considered for
hypoglycemia. surgical removal. However, biopsy or surgical resection of
Metformin is contraindicated in men with a serum any adrenal mass prior to ruling out a pheochromocytoma
creatinine level above 1.5 mg/dL (132.6 µmol/L) due to the is not recommended, as any manipulation of a catechol
possibility of lactic acidosis and will not address the under amine-secreting tumor without appropriate preoperative
lying problem of obesity. management can precipitate a hypertensive crisis.
Pramlintide slows gastric emptying, which can decrease Measurement of the plasma aldosterone to plasma renin
appetite. The weight loss associated with the use of pramlin ratio is indicated as part of the evaluation of an incidentally
tide is modest, and it may not be sufficient to improve the discovered adrenal mass in a patient with hypertension, but
metabolic abnormalities and obesity-related complications not in this individual who has normal blood pressure.
in this patient. In addition, the patient's hypoglycemia may Not performing additional testing may miss a subclin
be exacerbated by pramlintide. ical pheochromocytoma and would therefore not be an
KEY POINT
appropriate next step in management.
• Obese persons (BM! between 35 and 40) with type 2 KEY POINT
diabetes mellitus and associated complications should • A patient with an incidentally noted adrenal mass
be considered for bariatric surgery. should undergo biochemical testing for subclinical
Cushing syndrome and pheochromocytoma, and
Bibliography those with hypertension should also be evaluated for
Mechanick JI, Youdim A, Jones DB. el al. Clinical practice guidelines for the primary hyperaldosteronism.
perioperative nutritional, metabolic, and nonsurgical support of the
bariatric surgery patient-20l3 update: cosponsored by American
Association of Clinical Endocrinologisls. The Obesity Society. and Bibliography
American Society for Metabolic & Bariatric Surgery. Endocr Pract. 2013 Arnaldi G, Boscaro M. Adrenal incidentaloma. Best Pract Res Clin Endocrinol
Mar-Apr:19(2):337-72. [PMID: 23529351] Metab. 20l2: 26:405-419. [PMID: 22863384]
119
Answers and Critiques
Bibliography
Ng JM. Cooke M. Bhandari S. e1 al. The effec1 of iron and erythropoietin Item 53 Answer: A
treatment on the Ale of pa1ients with diabetes and chronic kidney Educational Objective: Manage diabetes mellitus
disease. Diabetes Care. 2010 Nov:33(11):2310-3. [PMID: 207983371
with continuous glucose monitoring.
120
Answers and Critiques
a subcutaneous needle. In some systems data recording can terminal hair growth will be slowed with combined oral con
be made available in real time to the patient, whereas other traceptive use. Oral contraceptives that contain 30 to 35 µg
models store the data for later access and analysis. Since she of ethinyl estradiol appear to be more effective in managing
does not have kidney disease or anemia that could affect hirsutism than formulations containing less ethinyl estradiol.
the accuracy of hemoglobin A,c measurements, she likely has Six months of treatment is considered the minimal interval in
episodes of hyperglycemia not detected by her current moni which to determine the level of response. Adherence to an oral
toring efforts. Fingerstick blood glucose values only provide a contraceptive regimen will provide this patient with predict
small snapshot of the glucose variability that occurs through able menses as well as contraceptive benefit. In addition, the
out the day. Undetected hyperglycemia or hypoglycemia can risk of endometrial hyperplasia is diminished.
lead to significant differences between the fingerstick blood Intermittent progesterone withdrawal, although effec
glucose values and the expected hemoglobin A,c level. Her tive for decreasing the risk of endometrial hyperplasia,
wide range of fasting blood glucose values could be indicative would have no effect on this patient's concern regarding
ofw1detected overnight hypoglycemia. Intermittent continu hirsutism.
ous glucose monitoring is recommended when postprandial The levonorgestrel intrauterine system is a long-acting,
hyperglycemia, dawn phenomenon, or overnight hypoglyce reversible contraceptive device that diminishes long-term
mia is suspected. risk of endometrial hyperplasia in patients with PCOS; how
Lifestyle modifications are recommended for glycemic ever, it provides no benefit for hirsutism and has no effect on
management; however, because this patient exercises in the androgen production.
evening, overnight hypoglycemia should be considered and Spironolactone is a potent antiandrogen and is very
evaluated with continuous glucose monitoring. Additional effective against male-pattern hirsutism in patients with
exercise may exacerbate the hypoglycemia. PCOS. However, it offers no benefit for control of the men
This patient does not have evidence of postprandial strual cycle. When spironolactone is prescribed, patients
hyperglycemia on her fingerstick blood glucose measure should be counseled regarding the potential teratogenicity
ments, although it could be missed since she only measures in male fetuses, and a concurrent reliable contraceptive
after her meals periodically. Given the discrepancy in her method should be established to prevent fetal exposure.
blood glucose values and A,c level, hypoglycemia should be Pregnancy can still occur in patients with oligo-ovulatory
ruled out first before increasing her insulin doses that may PCOS, and reliance on menstrual irregularity is not a substi
increase the risk of hypoglycemia. tute for a more proven contraceptive plan.
KEY POINT KEY POINT
• Continuous glucose monitoring may be useful in per • The combined oral contraceptive pill is the optimal
sons with postprandial hyperglycemia, dawn phe treatment to address both irregular menses and hir
nomenon, or overnight hypoglycemia. sutism in patients with polycystic ovary syndrome.
Bibliography Bibliography
Klonof DC, Buckingham B, Christiansen JS. et al. Continuous glucose Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop
f
monitoring: An Endocrine Society Clinical Practice Guideline. J Clin Group. Consensus on women·s health aspects of polycystic ovary syn
Endocrinol Metab. 2011; Oct:96(10):2968-2979. [PMID: 21976745] drome (PCOS). Hum Reprod. 2012 Jan;27(l):14-24. [PMID: 221479201
121
Answers and Critiques
can be added after a-blockade is achieved. Labetalol, a com hydrocortisone is adjusted based on symptoms, such as
bined a- and �-blocking agent, also can be used, especially orthostasis, weight loss, nausea, vomiting, and lighthead
in patients with tachyarrhythmias. A heart rate of 60 to 70/ edness. He does not have these symptoms, so his cortisol
min seated and 70 to 80/min standing can be targeted in most deficiency is adequately treated. Increasing his hydrocor
patients. Patients with pheochromocytoma who are normo tisone to higher than necessary doses increases the risk of
tensive also should be treated with a-blockers because they iatrogenic Cushing syndrome and glucocorticoid-induced
often become hypertensive during surgical resection. osteoporosis.
Increasing the dosage of lisinopril does not address the His testosterone value is normal, and he has normal
need for preoperative pharmacologic management of the morning erections. These are two signs that his hypogonad
patient's pheochromocytoma with a-blockade. ism is adequately treated. Possibly, his erectile dysfunction
Although indicated for tumor localization following is a result of fatigue from hypothyroidism or is functional
the biochemical diagnosis of pheochromocytoma, a con instead of physiologic.
trast-enhanced adrenal CT scan should not be performed There is no reason to stop somatropin. He has no evi
until after an a-adrenoceptor antagonist has been initiated. dence of residual tumor. Growth hormone (GH) replacement
Administering iodine contrast media to a patient who has can improve lean mass distribution and quality of life in a
not received a-blockade could incite a hypertensive crisis. patient with true GH deficiency, so it is reasonable to con
Similarly, the �-adrenoceptor antagonist propranolol tinue. Discontinuing GH will likely worsen his fatigue.
should not be given prior to a-blockade because unopposed
KEY POINT
a-adrenoceptor stimulation could also precipitate a hyper
tensive crisis. • Patients with secondary hypothyroidism from pitui
tary dysfunction have low or low-normal thyroid
KEY POINT
stimulating hormone values, so levothyroxine dose
• In patients with a confirmed diagnosis of pheochro should be adjusted based on free thyroxine (T4) level.
mocytoma, a-blockade should be instituted before
surgery to reduce the risk of cardiovascular complica Bibliography
tions and to control blood pressure. Schneider HJ, Aimaretti G, Kreitschmann-Andermahr, et al. Hypopituitarism.
Lancet. 2007 Apr 28;369(957l):1461-70. [PMID: l74675!7]
Bibliography
Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paragan
glioma: an endocrine society clinical practice guideline. J Clin Endocrinol Item 57 Answer: A
Metab. 2014 Jun;99(6):l9l5-42. [PMID: 24893135]
Educational Objective: Diagnose type 2 diabetes
mellitus.
122
Answers and Critiques
appropriate to repeat the abnormal screening test (fasting nadism with normal prolactin levels. Therefore, measurement
plasma glucose) that was already used for comparison. of serum prolactin is not the most useful test for this patient.
A random blood glucose measurement would be useful
KEY POINT
in this patient if he presented with classic hyperglycemic
symptoms in the setting of a blood glucose level of 200 mg/ • Klinefelter syndrome is a common cause of hypergo
dL (11.1 mmol/L) or above, as that would be diagnostic of nadotropic hypogonadism and azoospermia.
diabetes. This patient is not symptomatic.
Bibliography
KEY POINT
Krausz C, Chianese C. Genetic testing and counselling for male infertility.
• When discrepant results occur among different Curr Opin Endocrinol Diabetes Obes. 2014 Jun;21{3):244-50. [PMID:
24739313]
screening tests for diabetes mellitus, the American
Diabetes Association recommends repeating the
abnormal screening test. Item 59 Answer: D
Educational Objective: Interpret thyroid function test
Bibliography results in an elderly patient.
American Diabetes Association. (2) Classification and diagnosis of diabetes.
In: Standards of Medical Care in Diabetes-2015. Diabetes Care. 2015;38 Clinical follow-up with repeat measurement of thyroid-stim
Suppl l:SS-16. [PMID: 25537714]
ulating hormone (TSH) and free thyroxine (T 4) is the most
appropriate management for this patient. In persons over
80 years of age, the serum TSH level may be mildly elevated
Item 58 Answer: A above the typical reference range for younger adults. The
Educational Objective: Diagnose Klinefelter upper limit of the normal range in this elderly population
syndrome. without thyroid dysfunction may be as high as 8.0 µU/mL
(8.0 mUIL). Since this patient's TSH level is 6.4 µU/mL (6.4
The most appropriate diagnostic test to perform next is a
mU/L), his clinical symptoms are nonspecific, and his physi
karyotype. This patient has evidence of hypergonadotropic
cal examination is normal, additional evaluation or treatment
hypogonadism based on elevated gonadotropin levels and
is not indicated at this time. However, his clinical symptoms
low testosterone level. Klinefelter syndrome is a common
should be monitored, and his serum TSH and free T 4 levels
cause of hypergonadotropic hypogonadism and azoosper
should be measured repeatedly several times over a period of
mia, resulting in infertility. A 47,XXY karyotype is diagnostic
months to ensure that the TSH value is not part of a trend to
of Klinefelter syndrome. Mosaic variants of this condition
the development of overt thyroid dysfunction.
exist but typically present with oligoasthenospermia, testic
Because this patient's serum free T 4 level is normal and
ular failure, or hypogonadism. Concomitant symptoms often
a diagnosis of hypothyroidism has not been established, he
include sexual dysfunction and generalized fatigue. Tall stat
does not require levothyroxine therapy.
ure is a common finding. Patients with Klinefelter syndrome
Measurement of the serum total triiodothyronine (T)
may fail to achieve puberty or may present after sexual
level is not typically helpful in diagnosing hypothyroidism
maturation with azoospermia. Fertility may be achieved
because total T3 levels may remain within the normal range
from ejaculated sperm, if present, or extracted testicular
well into the evolution of hypothyroidism. However, total T 3
sperm; however, advanced reproductive techniques such as
levels are useful in evaluating patients with possible hyperthy
in vitro fertilization and intracytoplasmic sperm injection
roidism because the value may be elevated out of proportion to
are necessary to achieve pregnancy. Some couples may opt to
the T 4 level, and failure to recognize an elevated T 3 value may
include genetic testing by preimplantation genetic diagnosis
underestimate the degree of hyperthyroidism present.
and embryo biopsy to avoid transmission of the disorder to
Total T4 measures both the bound and unbound thyroid
subsequent generations. Typically, gonadotropin levels are
hormone fractions, whereas the free T4 reflects the unbound
high in patients with Klinefelter syndrome, representing
portion of hormone, and may more accurately reflect avail
testicular hypofunction. After plans for conception are com
able hormone levels in patients who may have an abnormal
pleted, supplementation with exogenous androgens may be
ity in protein metabolism (such as liver or kidney disease).
considered to prevent osteoporosis. Conception with donor
However, measurement of total T 4 in addition to free T 4 would
sperm is an alternative fertility treatment option.
not provide additional diagnostic information in this patient.
MRI of the pituitary would be needed only to rule out
a pituitary mass in the setting of hypogonadotropic hypogo KEY POINT
nadism. Because this patient's gonadotropin levels are high, • In patients over 80 years of age, the serum thyroid
a pituitary mass is unlikely. stimulating hormone level may be mildly elevated
Scrotal ultrasound would identify small testicles in a above the typical reference range.
patient with suspected Klinefelter syndrome, but it would not
identify the cause of this patient's elevated gonadotropin levels. Bibliography
Serum prolactin level would likely be normal, as Tabatabaie V, Surks Ml. The aging thyroid. Curr Opin Endocrinol Diabetes
Klinefelter syndrome is characterized by primary hypogo- Obes. 2013 Oct;20(5):455-9. [PMID: 23974775]
123
Answers and Critiques
Item 60 Answer: B this patient's tumor is invading the left cavernous sinus and
Educational Objective: Evaluate an incidentally
compressing the optic chiasm, complete resection will likely
noted adrenal mass.
not be possible; however, surgery can effectively debulk
the tumor and preserve vision in addition to significantly
The most appropriate diagnostic test to perform next is the decreasing growth hormone (CH) secretion as measured by
low-dose dexamethasone suppression test to screen for the insulin-like growth factor 1 (ICF-1) levels. In patients in whom
autonomous secretion of cortisol. The increasing use of imag complete resection is not possible, such as this patient, addi
ing studies for various medical indications has revealed oth tional therapy may be required such as stereotactic radiation
erwise unrecognized adrenal masses in less than 1% of the therapy or medical therapy to inhibit CH secretion or block its
population younger than 30 years and up to 7% of those older effect on the tissues. However, surgical resection remains an
than 70 years. Ten to 15% of adrenal incidentalomas are func essential first step in the treatment of acromegaly.
tional, although most have no overt clinical manifestations. A small number of CH-secreting pituitary adenomas
Therefore, testing is usually necessary to identify functional co-secrete prolactin. Although dopamine agonist therapy
tumors secreting catecholamines, cortisol, or aldosterone. Of with agents such as bromocriptine would treat the associ
the functional adenomas, most secrete excessive amounts of ated prolactin elevation, it is minimally effective in acromeg
cortisol. In subclinical Cushing syndrome (CS), classic signs aly and would not adequately treat CH secretion or address
or symptoms of cortisol excess are not observed; however, the mass effect of a CH-secreting adenoma.
complications of long-standing hypercortisolism may result. A CH receptor blocker, pegvisomant, is available. Peg
The patient has two disorders that can be seen in association visomant works in the peripheral tissues as an antagonist to
with subclinical CS: type 2 diabetes mellitus and osteoporosis. CH but does not decrease its production by the tumor. This
Obesity and hypertension are also common. The low-dose patient needs intervention to treat mass effect at this time
overnight dexamethasone suppression test is recommended because the tumor is damaging the optic chiasm and the
as the initial screening test for this condition due to its high patient's vision, and this treatment would not be expected
sensitivity. Screening for pheochromocytoma, such as by to decrease the tumor size.
measuring 24-hour urine fractionated metanephrines and Somatostatin analogues, such as octreotide and lan
catecholamines, is also indicated in all patients with an inci reotide, inhibit CH secretion and are helpful in treating
dentally noted adrenal mass. some patients with acromegaly. They are used primarily in
Adrenal vein sampling (AVS) is not needed. AVS is most patients with unresectable tumors without significant mass
often performed to evaluate for a bilateral versus unilateral effect or those with a contraindication to surgery. They may
adrenal cause of primary hyperaldosteronism. also be used in patients with continued CH secretion fol
Measurement of plasma renin activity and aldosterone lowing incomplete transsphenoidal resection. However, they
concentration is not indicated in patients without would not be an appropriate treatment in this patient with a
hypertension. large, invasive, vision-threatening pituitary tumor.
No further testing is also inappropriate. Although the Radiation therapy may be added to surgical or medical
imaging characteristics of the mass are in keeping with a therapy to help increase the chance for remission or cure.
benign adrenal adenoma, further diagnostic evaluation is Radiation to the pituitary carries a high risk of causing
needed. This includes testing for autonomous hormonal pituitary insufficiency and damage to surrounding tissues
secretion and subsequent radiographic surveillance (first at (particularly the optic nerves); therefore, it is not usually an
3-6 months and then annually for 1-2 years). initial treatment for acromegaly in most patients. In those in
KEY POINT
whom it is used, stereotactic surgery (gamma knife) is the
preferred approach to minimize potential complications.
• Ten to 15% of adrenal incidentalomas are functional; bio
chemical testing is needed to identify functional tumors KEY POINT
secreting catecholamines, cortisol, or aldosterone. • The primary therapy for acromegaly is transsphenoi
dal surgery to remove the causative growth hormone
Bibliography secreting pituitary adenoma.
Zeiger MA. Thompson GB. Duh QY, et al. The American Association of
Clinical Endocrinologists and American Association of Endocrine
Surgeons medical guidelines for the management ofadrenal incidentalo Bibliography
mas. Endocr Pract. 2009 Jul-Aug;lS Suppl 1:1-20. [PMID: 19632967} Melmed, S. Acromegaly pathogenesis and treatment. J Clin Invest. 2009
Nov;ll9:3189-202. [PMID: 19884662]
Item 61 Answer: E
Educational Objective: Treat acromegaly with Item 62 Answer: C
transsphenoidal pituitary surgery. Educational Objective: Treat high-risk thyroid cancer
postoperatively.
Transsphenoidal resection of the pituitary adenoma is the
initial treatment of choice in patients with acromegaly. It is Radioactive iodine (RAI) therapy is the most appropriate post
also the only treatment that is potentially curative. Because operative treatment in this patient who is at high risk of
124
Answers and Critiques
cancer recurrence based on his age, the size of the primary insulin is the recommended treatment. Unlike autoimmune
tumor, the presence of vascular invasion and extrathyroidal type 1 diabetes, chronic pancreatitis also destroys the pancre
extension, and the number of involved lymph nodes. He atic alpha cells causing a glucagon deficiency that increases
therefore may benefit from adjuvant RAJ therapy, which may the risk of spontaneous hypoglycemia. Glucagon acts on the
decrease the likelihood of recurrent disease in patients with liver to increase glucose production through glycogenolysis
nodal metastases. This is given in conjunction with levothy and gluconeogenesis. The recovery from hypoglycemia is also
roxine suppression therapy, which is indicated in all patients impaired with alpha cell destruction. Early recognition of
who have had a total thyroidectomy. Because of his high-risk hypoglycemic symptoms and strategic hypoglycemic treat
disease, it would be appropriate to lower the thyroid-stimu ment plans should be emphasized with patients with pancre
lating hormone level to less than 0.1 µU/mL (0.1 mU/L) in the oprivic diabetes.
absence of contraindications such as pre-existing cardiovas Exenatide, a glucagon-like protein-1 (GLP-1) mimetic,
cular disease or age greater than 65 years. suppresses glucagon and promotes insulin secretion. The
Traditional chemotherapeutic agents, such as doxoru pancreatic beta cell and alpha cell destruction associated
bicin, are generally ineffective in the management of differ with chronic pancreatitis precludes this treatment option.
entiated thyroid cancer and would not be indicated for this Postmarketing reports of pancreatitis are also cause for con
patient. In patients with anaplastic carcinoma of the thyroid, cern for the use of this class of medication in patients with a
however, some studies have demonstrated a possible benefit history of pancreatitis.
with concomitant use of paclitaxel-based chemotherapy and The sulfonylurea glipizide increases insulin secretion.
external-beam radiotherapy. This patient has classic pap The effect would likely be minimal to nonexistent in this
illary thyroid cancer histology and would not benefit from patient with hyperglycemia resulting from substantial beta
such treatment. cell destruction from chronic pancreatitis.
External-beam radiotherapy is rarely used in patients Metformin decreases hepatic glucose output by inhibit
with differentiated thyroid cancer. An exception would be ing gluconeogenesis and increases insulin-mediated glucose
the management of patients with inoperable disease that utilization in peripheral tissues. Metformin is a first-line
threatens to cause local extension into vital structures in the agent for initial treatment of type 2 diabetes; however, this
neck such as the trachea, esophagus, or major blood vessels. patient has an insulin deficiency from pancreatic beta cell
Because of the extent of disease found at surgery and destruction and should be treated as a patient with type 1
this patient's high risk of recurrence, providing no addi diabetes.
tional therapy would not be an appropriate next step in
KEY POINT
management.
• Hyperglycemia caused by chronic pancreatitis is an
KEY POINT acquired form of type 1 diabetes mellitus and should
• A patient who has undergone total thyroidectomy be treated with insulin.
for thyroid cancer and is at high risk for disease
recurrence should receive adjuvant radioactive Bibliography
iodine therapy. Mergener K, Baillie J. Chronic pancreatitis. Lancet. 1997 Nov 8;350(9088):
1379-85. [PMID: 9365465]
Bibliography
Jonklaas J, Sarlis NJ, Litofsky D, et al. Outcomes of patients with differenti A
ated thyroid carcinoma following initial therapy. Thyroid. 2006 Dec;l6(12):
Item 64 Answer:
1229-42. [PMID: 17199433] Educational Objective: Treat infertility related to
polycystic ovary syndrome.
125
Answers and Critiques
after several failed cycles of ovulation induction with clomi KEY POINT
phene citrate.
• Microprolactinomas in asymptomatic patients do not
In patients with clomiphene resistance, gonadotropin
require treatment; however, surveillance is recom
therapy would be an appropriate next step; however, caution
mended.
is warranted because higher-order multiple gestation may
result.
A 2012 Cochrane review of the effect of insulin-sensi Bibliography
Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of
tizing drugs in women with infertility and PCOS included hyperprolactinemia: an Endocrine Society clinical practice guideline. J
44 trials, the majority of which involved metformin. Rates Clin Endocrinol Metab. 2011 Feb:96(2):273-88. [PMID: 21296991]
of pregnancy were improved with metformin compared
with placebo and metformin plus clomiphene compared
with clomiphene alone, but metformin did not change rates Item 66 Answer: B
of live births compared with placebo or with clomiphene Educational Objective: Manage diabetic neuropathy.
compared to clomiphene alone.
Duloxetine is a reasonable initial option for this patient's pain
KEY POINT ful peripheral neuropathy. The typical presentation for distal
• Selective estrogen receptor modulators such as clomi symmetric polyneuropathy is a bilateral "stocking-glove" dis
phene citrate are the established first-line treatment tribution. Damage to the small nerve fibers can result in pain,
for ovulation induction in anovulator y patients with numbness, burning, and tingling. It can also impair light touch
infertility from polycystic ovary syndrome. and temperature sensation. Damage to the large nerve fibers
leads to abnormal vibration sensation and proprioception.
Diminished or loss of ankle reflexes is commonly seen early
Bibliography
Legro RS, Brzyski RG, Diamond MP, et al: NlCHD Reproductive Medicine
with diabetic polyneuropathy. Motor weakness can occur as
Network. Letrozole versus clomiphene for infertility in the polycystic the polyneuropathy progresses. Several classes of drugs are
ovary syndrome. N Engl J Med. 2014 Jul 10;371(2):119-29. Erratum in: frequently used for symptomatic pain relief, including the tri
N Engl J Med. 2014 Oct 9;317(15):1465. [PMID: 25006718]
cyclic antidepressants (amitriptyline), other classes of antide
pressants (duloxetine, venlafaxine), anticonvulsants (pregaba
lin, gabapentin, valproate), and capsaicin cream. There are few
Item 65 Answer: C head-to-head comparison trials for these classes of drugs for
Educational Objective: Treat a microprolactinoma in distal symmetric polyneuropathy, thus selection must take into
a postmenopausal woman. consideration the potential risks and benefits associated with
each drug for an individual patient. Duloxetine has fewer risks
No therapy is necessary at this time, and the patient should
than amit1iptyline for this patient given his cardiac history.
be retested in 12 months. The patient has a microprolac
Tricyclic antidepressants, such as amitriptyline, should
tinoma, but she is postmenopausal. Luteinizing hormone
be used cautiously in patients with known cardiac dis
and follicle-stimulating hormone levels are normally high
ease due to an association between this class of drugs and
in postmenopausal women because of ovarian failure; how
arrhythmias, heart block, and sudden death. The patient's
ever, her levels are lower than expected, likely because the
history of cardiac disease and a first-degree atrioventricular
elevated prolactin is providing negative feedback. This causes
block may increase his risk of side effects from amitriptyline.
hypogonadism but is not clinically relevant because she is
A nerve conduction study is not routinely required for
already hypogonadal from normal menopause. She has mini
diagnosis or management in patients with diabetes with a
mal symptoms from menopause and is tolerating it well.
typical presentation of symmetric distal polyneuropathy.
The prolactinoma was found incidentally. On MRI, it
Atypical clinical features should prompt additional work-up,
has no concerning features, and her other pituitary hormone
including electrophysiologic testing.
levels are normal. Although no treatment is necessary for
Vitamin B 12 deficiency has been associated with long-term
this asymptomatic patient, it is advisable to retest in 6 to
use of metformin and can present with peripheral neuropathy.
12 months to make sure that the tumor does not grow.
It is also commonly seen in the setting of megaloblastic anemia.
Dopamine agonists, such as cabergoline, are used to
treat symptomatic prolactinomas, but it is not necessary in It is unlikely that vitamin B 12 deficiency is the cause of this
patient's peripheral neuropathy as he has a classic presentation
this asymptomatic patient.
for symmetric distal polyneuropathy, discontinued metformin
Radiosurgery is not necessary. It is an option to treat
2 years ago, and has a normal complete blood count.
pituitary tumors that are not amenable to standard surgery
or cannot be fully resected, but it is not indicated for this KEY POINT
asymptomatic patient. • Treatment options for diabetic polyneuropathy include
Transsphenoidal resection of the pituitary tumor is the tricyclic antidepressants, other classes of antidepres
overly invasive and unnecessary because she is doing well.
sants (duloxetine, venlafaxine), anticonvulsants (pregab
In addition, first-line therapy for symptomatic prolactino
alin, gabapentin, valproate), and capsaicin cream.
mas are dopamine agonists, not surgery.
126
Answers and Critiques
127
Answers and Critiques
128
Answers and Critiques
that remains above goal despite concurrent use of three antihy adenomatous hyperplasia, and the sonographic features of
pertensive agents of different classes, one of which is a diuretic. the gland and slow progression of the compressive symptoms
Resistant hype11ension may occur in as many as 10% of patients support a diagnosis of a benign lesion. He has evidence of
with hypertension. Although this patient is being treated with compressive symptoms on physical examination, with facial
a diuretic, he has significant hypokalemia in the presence of flushing when raising his arms (Pemberton sign). The flush
treatment with an ACE inhibitor and potassium supplementa ing indicates venous outflow obstrnction by the goiter as
tion. This raises the possibility of primary hyperaldosteronism the vessels course through the thoracic inlet. Additionally,
as a cause or contributing factor of his resistant hypertension. his symptoms of dysphagia and change in voice quality may
Appropriate initial evaluation for this diagnosis is measure suggest a compressive effect on the esophagus and recurrent
ment of the plasma aldosterone-plasma rerlin activity ratio. la1yngeal nerves, respectively. Surgical removal of the thyroid
If positive, confirmatory testing is usually accomplished with offers the best option for immediate relief of symptoms and
intravenous salt loading, fludrocortisone suppression testing, identification of a possible underlying malignancy.
or captopril testing. If confirmed, adrenal imaging is indicated External-beam radiotherapy can result in eventual
to determine if hyperaldosteronism is due to a bilateral or uni shrinkage of the thyroid but will not provide immediate
lateral cause. Mineralocotticoid receptor antagonists (such as relief of his obstructive symptoms, is unlikely to be curative,
spironolactone) are indicated for patients with a bilateral cause potentially increases the risk of secondary malignancy, and
of p1irnary hyperaldosteronisrn and those with a wulateral is associated with significant morbidity.
cause who refuse or are not candidates for surgery. Levothyroxine therapy has been shown to reduce thy
Dexamethasone suppression testing is used to evaluate roid volume by up to 20%, but the clinical significance of this
for glucocorticoid excess. However, this patient is not taking small change in volume with such a large goiter is unlikely to
exogenous glucocorticoids and has no physical examina improve symptoms. Additionally, levothyroxine therapy may
tion findings (fat redistribution, striae) or laboratory stud take many months to years to reduce the thyroid volume,
ies (glucose metabolism abnormalities) suggesting Cushing and this patient needs immediate relief of his obstructive
syndrome. Therefore, testing for this possibility is not an symptoms.
appropriate next step in diagnosis. Radioactive iodine has been used to shrink multinod
Measurement of plasma metanephrines and catechol ular goiters; the volume change is also gradual and optimal
amines is used to evaluate for the possibility of pheochrorno reduction averages 40%. However, radioactive iodine ther
cytoma, which classically presents with the triad of diapho apy may be risky in this patient because acute swelling of
resis, headache, and tachycardia, none of which are present the thyroid after iodine uptake can lead to compromise of
in this patient. In addition, pheochromocytoma would not the vascular structures at the level of the thoracic inlet and
explain the patient's hypokalemia. further compression of the trachea.
Renal artery Doppler flow studies may be helpful in
KEY POINT
evaluating for renovascular hypertension. However, most
cases of renovascular hypertension occur in patients over • In patients with multinodular goiter with compressive
50 years of age and are associated with atherosclerotic car features, thyroidectomy is most likely to provide
diovascular disease or evidence of functional impairment immediate relief of symptoms, decrease the risk
of the kidney, neither of which are apparent in this patient. of fatal airway compromise, and possibly identify
underlying malignancy.
KEY POINT
129
Answers and Critiques
include diagnostic laparoscopy, but this is not typically per and pheochromocytoma. Failure to identify and treat a pheo
formed as first-line evaluation given the need for general chromocytoma prior to surgery can result in an intraoperative
anesthesia, intubation, and recovery. Repair of the fallopian hypertensive c1isis and, potentially, death.
tubes may be possible with microsurgical techniques; how While it is important to assess the risk of metastatic
ever, reocclusion is possible and the risk of subsequent ectopic disease in this high-risk patient, 18-fluoro-deoxyglucose
pregnancy is high. Many women elect to proceed with in vitro positron emission tomography scanning is not the ideal
fertilization in lieu of tubal surgery. imaging modality in patients with MTC, as there is a high
Ovarian reserve assessment and semen analysis are false-negative rate. CT of the lungs and liver is a more effec
essential when evaluating a couple with infertility. Ovarian tive means of identification of distant metastases .
reserve assessment can be accomplished with early follicu While evaluation for hyperparathyroidism by measur
lar phase testing of follicle-stimulating hormone (FSH) or ing the serum parathyroid hormone level is indicated in this
anti-miillerian hormone (AMH). Transvaginal ultrasound patient with MEN2A, it is not the most appropriate next step
in the early follicular phase allows for counting of antral in management. Testing for hyperparathyroidism is recom
follicles in each ovary, which if present at greater than eight mended prior to surgery because the parathyroid disease
bilaterally support normal ovarian reserve. However, given can be managed simultaneously with the thyroid cancer, but
this patient's history of pelvic inflammatory disease and her would not be an appropriate step before evaluating a patient
husband's history of fathering a child in a previous marriage. with MEN2A for the presence of pheochromocytoma.
HSG is the diagnostic test that is most likely to reveal an Total thyroidectomy and lateral neck dissection should
abnormality. not be performed until it is confirmed that this patient does
Semen analysis can be performed after a short window not have a coexisting endocrine neoplasm owing to the high
of abstinence on an ejaculated sperm specimen. However, it intraoperative risk associated with untreated pheochromo
is unlikely to be helpful in this patient's husband. cytoma. If identified, pheochromocytomas should be surgi
Karyotyping is usually not indicated as part of the initial cally removed prior to thyroidectomy.
evaluation of unexplained female infertility because of the Genetic counseling is a very important component of
low incidence of discovered abnormalities. the treatment plan for all patients with newly diagnosed
Specialized laboratories with andrology services eval MEN2A as first-degree relatives are at high risk for also hav
uate sperm concentration, sperm motility, and sperm mor ing the RET mutation. With a nearly 100% penetrance for
phology. Ovarian reserve may be evaluated by serum testing development of MTC in carriers of RET mutations, referral to
(day 3 follicle-stimulating hormone level, AMH level) or by a team with experience in the management of these disor
transvaginal ultrasound assessment of antral follicle count. ders is critical for timely diagnosis and treatment.
KEY POINT KEY POINT
• Primary infertility due to a tubal abnormality is com • All patients with multiple endocrine neoplasia type
mon, particularly in women with a history of pelvic 2A should undergo testing to exclude pheochromocy
inflammatory disease, and is best evaluated with a toma prior to thyroidectomy; an elevated level of
hysterosalpingogram. plasma fractionated metanephrines should prompt
treatment for pheochromocytoma before addressing
Bibliography the thyroid malignancy.
Maheux-Lacroix S. Boutin A. Moore L. et al. Hysterosalpingosonogrnphy for
diagnosing tubal occlusion in subfertile women: a systematic review
with meta-analysis. Hum Reprod. 2014 May:29(5):953-63. [PMID: Bibliography
24578476] American Thyroid Association Guidelines Task Force,2015 Thyroid. [PMID:
25810047]
Item 74 Answer: B
Educational Objective: Evaluate newly diagnosed
Item 75 Answer: C
Educational Objective: Treat severe hypercalcemia.
Cl
medullary thyroid cancer.
This patient has severe. malignancy-relaied (non-parathy
The next most appropriate step in the management of this roid hormone [PTI i J-mcdiatcd) hypercalccrnia with associ
patient with medullary thyroid cancer (MTC) and multiple ated mental status changes and acute kidney injury. Hemo
endocrine neoplasia type 2A (MEN2A) is to evaluate for the dialysis is generally reserved for patienls wilh extremely
presence of a pheochromocytoma by measurement of fraction high scrum calcium levels (>18 mg dL [4.5 mmol L]) asso
ated plasma metanephrines. All patients with a cytologic diag ciated wi!h c1cure kidney injury !hat precludes o!her acute
nosis of MTC should undergo testing of the tumor for genetic treatments becc1use it is able to rnpidly lower serum cal
abnormalities as the initial step in their evaluation as 25% of cium and provide cc1reful mc1nagement of volume status
patients with MTC will have the inherited form. Identification ,rnd electrolytes. Both hemodialysis and peritoneal dialysis
of a RETmutation in this patient means that the he has MEN2A, 8re options. although hemodialysis more rapidly lowers
an inherited syndrome associated with hyperparathyroidism cc1lcium levels.
130
Answers and Critiques
Cl osteoclast
CONT.
Calcitonin is a rapidly acting agent Lhal inlerleres wiLh
function and promotes kidney excretion of cal
Continuing the current regimen places the patient at
increased risk for continued hypoglycemia in the setting of
cium. However. its calcium-lowering effecl is relatively hypoglycemic unawareness.
weak. and it is only able to lower serum calcium levels by I to Increasing the metformin dose may improve insulin
2 mg/dL (0.25-0.50 mmol/L) over 4 Lo 6 hours. which would sensitivity and decrease hepatic gluconeogenesis, which
not be optimal lowering of this palienrs very high calcium could improve the hyperglycemia and/or worsen the hypo
level. Calcilonin will bring her calcium levels down. but nol glycemia. An increased metformin dose does not address the
enough to alleviate her symptoms. serious complication of hypoglycemic unawareness, which
Cinacalcel. a calcimimetic agent. is an option for lower must be corrected first.
ing calcium for symptomatic patienls. but it is nol indicated Pramlintide could decrease the hemoglobin A 1e to
to acutely reduce life-Lhreatening hypercalcemi,1. the patient's goal; however, hypoglycemia is a side effect
Intravenous bisphosphonales are used fcir Lrealmenl or of pramlintide in conjunction with insulin use. This may
malignancy-induced hypercalcemia. with zoledronic acid further increase the risk of hypoglycemia in this scenario.
or pamidronate the most common agenls. However. onset or Pramlintide is an amylin mimetic that decreases glucagon
action is nol rapid. and bisphosphonales are conlraindicalecl secretion and increases satiety by decreasing gastric emp
in severe kidney injury. Therefore, zoleclronic acid would not tying. Pramlintide should be considered when the intended
be an appropriate next step in lreatmenl. reduction in hemoglobin A 1e is modest and the desired
Once the serum calcium has been lowered by dialysis. effects are a reduction in both weight and postprandial
calcitonin or an intravenous bisphosphonale may be used hyperglycemia.
to keep the calcium levels al a manageable level. The use or
KEY POINT
dialysis in the patient is strictly for resolution of Lhe acute
mental status changes from Lhe elevaled calcium level, and • Treatment for hypoglycemic unawareness is to reduce
longer-term management of hypercalcemia is requi reel. the insulin dose and allow permissive hyperglycemia
at all times for several weeks to provide the body an
KEY POINT
opportunity to reset the counterregulatory response
• For patients with serum calcium levels greater than to hypoglycemia to a more appropriate blood glucose
18 mg/dL (4.5 mmol/L) with neurologic symptoms or range.
acute kidney injury, hemodialysis is an appropriate
choice to quickly reduce calcium levels. Bibliography
Cryer PE, Axelrod L. Grossman AB. et al. Evaluation and management of
Bibliography adult hypoglycemic disorders: an Endocrine Society Clinical Practice
Guideline. J Endocrinol Metab. 2009 Mar;94(3):709-28. [PMID: 19088155]
Rosner MH, Daikin AC. Onco-nephrotogy: the pathophysiology and treat
ment of malignancy-associated hypercalcemia. Clin J Am Soc Nephrol.
2012:7:1722-9. [PMID: 22879438]
Item 77 Answer: C
Educational Objective: Diagnose elevation of lutein
Item 76 Answer: D izing hormone related to polycystic ovary syndrome.
Educational Objective: Treat hypoglycemic
The most likely cause of this patient's false-positive results
unawareness.
using the urinary luteinizing hormone (LH) kit is polycystic
This patient should decrease his meal-time insuHn and con ovary syndrome (PCOS). Women with PCOS typically have
tinue metformin. He has hypoglycemic unawareness sec elevated resting LH levels, which may be mistaken on home
ondary to a diminished counterregulatory response that has urinary LH kits for ovulation. The primary clinical manifes
developed in the setting of repeated episodes of hypoglyce tations of PCOS are menstrual irregularity (oligomenorrhea
mia. His hypoglycemia occurs in the postprandial state, thus or amenorrhea), ovulatory dysfunction with resultant infer
the meal-time insuHn should be decreased to allow permis tility, insulin resistance, and hyperandrogenism. Oligo-ovu
sive hyperglycemia for 2 to 3 weeks. Permissive hyperglycemia lation or anovulation can result in endometrial hyperplasia
is defined as allowing an increase in blood glucose values to and/or infertility. Hyperandrogenism presents as hirsutism,
the level at which no further episodes of hypoglycemia occur. acne, or androgenic alopecia. Most patients with PCOS also
Using less stringent glycemic goals during this period will have insulin resistance, and studies have shown an increased
provide the body an opportunity to reset the counterregula incidence of metabolic syndrome, obesity, impaired glucose
tory response to hypoglycemia to a more appropriate blood tolerance, and frank type 2 diabetes mellitus. PCOS remains
glucose range, if possible. Although developing mutual hemo a diagnosis of exclusion that is made both clinically and with
globin A1e goals with the patient is important, hypoglycemia ancillary testing. A patient with PCOS with a positive urinary
in this scenario precludes reaching his goal safely. Once he no LH measurement result may interpret this as a true LH surge
longer has hypoglycemia, changes to the meal-time insulin and expect ovulation to be imminent. Attempts at conception
doses or to meal content and volume can be evaluated to fine with intercourse or insemination may be focused on this
tune his regimen while avoiding hypoglycemia. reading and may therefore be ineffective. A more accurate
131
Answers and Critiques
assessment of LH surge and anticipated ovulation in patients Denosumab is a receptor activator of nuclear factor KB
with PCOS would be through transvaginal identification of (RANK) ligand inhibitor FDA approved for the treatment of
ovarian folliculogenesis and confirmatory serum assessment osteoporosis in postmenopausal women who are at high risk
of reproductive hormones. of fracture. Since this patient has not failed bisphosphonate
Late-onset (nonclassic) congenital adrenal hyperplasia, therapy (shown a significant decrease in BMD while on
although a common cause of hirsutism and oligo-ovulation, bisphosphonate therapy) nor is she intolerant of the current
is typically associated with normal or low LH levels owing to therapy, there is no reason to change her therapy.
the negative feedback of elevated androgens of adrenal origin Teriparatide is appropriate as first-line therapy for
on the anterior pituitary. patients at high risk for fracture (T-score < -3.0) or who
Functional hypothalamic amenorrhea affects 3% of have experienced progressive osteoporotic disease while
women between the ages ofl8 and 40 years and is a diagno on bisphosphonate therapy. This change would be unnec
sis of exclusion. Risk factors for this condition include a low essary since the patient's BMD has been maintained for the
body weight and fat percentage, rapid and substantial weight past 5 years.
loss, eating disorders, excessive exercise, severe emotional A drug holiday is indicated for patients who have been
stress, severe nutritional deficiencies, and chronic or acute on bisphosphonate therapy for 3 to 5 years, have had no
illness. FSH and LH levels are inappropriately low or normal progression of the disease, and have minimal risk factors
and cannot account for a positive urinary LH test. for additional fractures. TI1is patient has multiple risk fac
Hypothyroidism and elevated serum prolactin levels tors for fractures; therefore, a drug holiday would not be
suppress rather than elevate serum LH levels and would not appropriate.
account for this patient's increased urinary LH measurement.
KEV POINT
KEV POINT • In patients at high risk for osteoporosis, it is appropri
• Women with polycystic ovary syndrome typically ate to continue bisphosphonate therapy alone if ade
have elevated resting luteinizing hormone (LH) levels, quate bone stability has been achieved.
which may be mistaken on home urinary LH kits for
ovulation. Bibliography
National Osteoporosis Foundation (www. my.nof.org/bone-source).
Clinician's Guide to Prevention and Treatment of Osteoporosis.
Bibliography Washington. DC: National Osteoporosis Foundation: 2014.
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.
Revised 2003 consensus on diagnostic criteria and long-term health risks
related to polycystic ovary syndrome. Fertil Steril. 2004 Jan:81(1):19-25. Item 79 Answer: D
[PMID: 14711538]
Educational Objective: Manage primary
hyperaldosteronism.
Item 78 Answer: C
The most appropriate treatment for this patient is spironolac
Educational Objective: Treat a high-risk patient with
tone. He has primary hyperaldosteronism (PA) due to a bilat
osteoporosis.
eral adrenal source as evidenced by the Jack of lateralization
After counseling about smoking cessation. this patient on adrenal vein sampling (AVS). Bilateral adrenal hyperplasia
should continue her current alendronate therapy. She has is the most common etiology of PA. accounting for approxi
documented osteoporosis and is at high risk for subsequent mately 60% of cases, and spironolactone is the treatment of
fractures due to multiple risk factors, including current choice. Spironolactone is a mineralocorticoid receptor (MR)
smoking and a previous fracture. Her bone mineral density antagonist that can improve blood pressure, normalize serum
(BMD) has been well maintained on an oral bisphosphonate potassium concentration, and reduce excess cardiovascular
for the last several years. The best way to evaluate a dual-en risk related to hyperaldosteronism. Eplerenone is an alterna
ergy x-ray absorptiometry (DEXA) scan from measurement tive MR antagonist that is less likely to cause gynecomastia
to measurement is to compare the bone mineral density in men because of greater MR selectivity; however, use of
readings from year to year, not the T -score. A change in BMD eplerenone for this indication is off-label. Antagonists of the
that is less than about 4% (or the percentage noted by the aldosterone-sensitive sodium channel (amiloride) can be used
DEXA machine manufacturer) is not considered a statisti as second-line therapy.
cally significant change. This regimen should be considered Bilateral adrenalectomy is not appropriate for the rou
successful therapy since the goal of bisphosphonates is not to tine management of PA, as this would risk primary adrenal
build bone mass but to stabilize bone loss. Since this patient failure, thus necessitating life-long glucocorticoid and min
has had stable BMD while on alendronate. there is no indi eralocorticoid therapy.
cation to convert to a more invasive, expensive option at this Dexamethasone, a long-acting synthetic glucocorticoid,
time. It will be important, however, to continue to follow her has a role in treating only a small percentage of patients who
for atypical fractures of the long bone due to her prolonged have glucocorticoid-remedial hypertension, a very rare auto
bisphosphonate treatment. lf leg pain or an atypical fracture somal dominant condition resulting from ectopic expres
is noted, bisphosphonate therapy should be discontinued. sion of aldosterone synthase in the cortisol-producing zona
132
Answers and Critiques
fasciculata. Administration of dexamethasone will suppress TI1ere is no indication for pituitary MRI at this time
pituitary adrenocorticotropic hormone (ACTH) secretion in because her hyperprolactinemia is explained by hypothy
these patients and therefore mineralocorticoid production. roidism. It is necessary to make sure that her hyperprolactin
However, hyperaldosteronism in most patients is indepen emia normalizes after treatment with levothyroxine.
dent of ACTH secretion, and suppression with exogenous
KEY POINT
glucocorticoid is not an effective therapy.
Left adrenalectomy should not be performed because • In patients with hyperprolactinemfa and hypothy
the patient has a bilateral cause of PA. The left adrenal roidism, the hypothyroidism should be treated first,
adenoma detected by CT scan is an incidental finding and then the patient should be reevaluated to ensure that
is likely not the cause of this patient's hyperaldosteronism. the hyperprolactinernia resolves.
Because nonsecreting adrenal adenomas are common, AVS
is needed in most patients with hyperaldosteronism to Bibliography
determine the source of aldosterone secretion when imag Melmed S. Casanueva FF. Hoffman AR, et al. Diagnosis and treatment of
ing studies show an adrenal adenoma to assess its contri hyperprolactinemia: An Endocrine Society clinical practice guideline.
J Clin Endocrinol Metab. 2011 Feb:96(2):273-88. [PMID: 21296991]
bution to excess mineralocorticoid production. AVS should
be done at a high-volume referral center due to a high risk
of complications when significant procedural experience
Item 81 Answer: B
is lacking.
Educational Objective: Diagnose cystic fibrosis as a
KEY POINT cause of congenital bilateral absence of the vas def
• For patients with primary hyperaldosteronism due to erens and azoospermia.
bilateral adrenal hyperplasia, medical therapy with a Congenital bilateral absence of the vas deferens is a common
mineralocorticoid antagonist such as spironolactone is cause of obstructive azoospermia and is frequently associated
the treatment of choice because of its proven efficacy with cystic fibrosis (CF). It may also present with unilateral
to lower blood pressure, normalize serum potassium absence of the vas deferens. Many patients are unaware that
concentration, and reduce cardiovascular risk. they have CF because they may have a mild form that causes
only nonspecific symptoms such as chronic sinusitis. Partner
Bibliography testing for CF-carrier status should be encouraged to assess
Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis. and treat the likelihood of transmission to a subsequent generation.
ment of patients with primary aldosteronism: an endocrine society
clinical practice guideline. J Clin Endocrinol Metab. 2008 Sep;93(9):3266- Sperm production is often normal in these patients; however,
81. [PMID: 185522881 the absence of the vas deferens limits any observable sperm
in the ejaculate. Therefore, testicular biopsy is necessary to
retrieve sperm for use in advanced reproductive techniques
Item 80 Answer: B (ART) such as in vitro fertilization and intracytoplasmic sperm
injection. Utilization of donor sperm is an alternative for cou
Educational Objective: Manage hyperprolactinemia
ples not interested in ART.
caused by hypothyroidism.
Androgen abuse is common among elite and profes
TI1e most appropriate treatment for this patient is to begin sional athletes and in young men. Physical examination
levothyroxine. She has primary hypothyroidism with an findings may include excessive muscular bulk, acne, gyneco
elevated thyroid-stimulating hormone level and a low free mastia, and decreased testicular volume. Low sperm counts
thyroxine (T4 ) level. Her symptoms are consistent with hypo also may be present with exogenous androgen use. Andro
thyroidism. Hypothyroidism is a cause of hyperprolactin gen abuse can result in hypogonadism and infertility, which
emia. When patients present with hyperprolactinemia and occasionally are irreversible. TI1is patient's normal physical
hypothyroidism, the hypothyroidism should be treated and examination, normal testicular volume, and absence of the
then the patient should be reevaluated to ensure that the vas deferens argue against this diagnosis.
hyperprolactinemia resolves. The patient's pituitary gland is Primary hypogonadism is due to testicular failure and
normal. There is no tumor. is defined as a low testosterone level with elevated lutein
The hypothyroidism should be treated first, and then izing hormone and follicle-stimulating hormone levels.
the patient's prolactin level should be retested. There is no Primary hypogonadism can have congenital or acquired
indication for cabergoline, a dopamine agonist. at this point. causes. TI1e most common congenital cause is Klinefelter
Cabergoline is an appropriate therapy for a patient with syndrome (47,XXY karyotype). 11,e extra sex chromo
hyperprolactinemia caused by a prolactinoma. This patient's some results in malformation of the seminiferous tubules
hyperprolactinemia is explained by hypothyroidism. and typically of the Leydig cells. Physical examination is
Sertraline does not cause hyperprolactinemia or hypo likely to reveal small. firm testes and decreased virilization.
thyroidism. Antipsychotic agents are a common cause of Additional manifestations include oligospermia and infer
hyperprolactinemia, but selective serotonin reuptake inhib tility. Klinefelter syndrome does not result in obstructive
itors such as sertraline are not. azoospermia due to absence of the vas deferens.
133
Answers and Critiques
A clinically palpable varicocele typically affects fertility early morning serum cortisol level is unequivocally low, as
by lowering sperm motility through a local heat effect. A in this patient.
scrotal bulge may be noted by the clinician, and the patient Measurement of the plasma ACTH level is used to dif
may note pain that is worse with the Valsalva maneuver. ferentiate primary adrenal failure from other causes of low
Azoospermia would not be caused by varicocele alone. cortisol. In primary adrenal failure, the plasma ACTH level is
Y chromosome microdeletions can be associated with typically significantly elevated (200 pg/mL [44 pmol!L]) and
oligospermia or azoospermia and small testicular volume. would confirm the diagnosis. However, withholding ther
This chromosomal abnormality is not associated with apy while awaiting diagnostic confirmation would not be
absence of the vas deferens and is therefore not a likely cause appropriate because of the potential life-threatening nature
of this patient's findings. of primary adrenal failure.
Although prednisone is an acceptable agent for glu
KEY POINT
cocorticoid replacement, it has almost pure glucocorticoid
• Congenital bilateral absence of the vas deferens is a activity and would not be an appropriate single agent for
common cause of obstructive azoospermia and is fre treatment of primary adrenal failure in which replacement
quently associated with cystic fibrosis. of both glucocorticoid and mineralocorticoid is required.
KEY POINT
Bibliography
Stahl PJ, Schlegel PN. Genetic evaluation of the azoospermic or severely • Cortisol replacement therapy should be initiated
oligozoospermic male. Curr Opin Obstet Gynecol. 2012 Aug;24(4):221-8. immediately in persons with confirmed adrenal insuf
[PMID: 227290881
ficiency, which is diagnosed by an early morning
serum cortisol level below 3 µg/dL (82.8 nmol/L) in the
setting of signs and symptoms of cortisol deficiency.
Item 82 Answer: B
Educational Objective: Manage primary adrenal failure.
Bibliography
Initiation of cortisol replacement therapy with a glucocor Neary N. Nieman L. Adrenal insufficiency: etiology, diagnosis and treatment.
Curr Opin Endocrinol Diabetes Obes. 2010 Jun;l7(3):217-23. [PMID:
ticoid (such as hydrocortisone) and mineralocorticoid (such 20375886]
as fludrocortisone) is the most appropriate next step in man
agement. This patient has symptoms consistent with adre
nal insufficiency (fatigue, unintentional weight loss, nausea, Item 83 Answer: A
and vomiting); her family history of autoimmune disorders,
Educational Objective: Manage the "honeymoon"
hyperpigmentation noted on physical examination, and
phase of type 1 diabetes mellitus.
hyperkalemfa on laboratory testing suggest primary adrenal
failure. Patients with primary adrenal failure frequently have The most appropriate management for this patient's hypo
increased pigmentation over the extensor surfaces and buccal glycemia is to decrease insulin glargine and insulin aspart.
mucosa due to the excessive secretion of melanocyte-stim The glucose toxicity present at the time of diabetic ketoaci
ulating hormone, which shares a common precursor with dosis has diminished with an intensive insulin regimen. Her
adrenocorticotropic hormone (ACTH). Hyperkalemia occurs remaining functional pancreatic beta cells have regained the
due to deficiency of aldosterone. 'TI1e diagnosis of adrenal ability to produce some insulin in the "honeymoon" phase,
insufficiency is made by documenting an inappropriately low which explains the hypoglycemia on previously well-toler
serum cortisol level. An early morning serum cortisol level ated doses of insulin. The decreased need for insulin will not
that is less than 3 µg/dL (82.8 nmol/L) in the setting of signs be long term as pancreatic beta cells continue to be destroyed
and symptoms of cortisol deficiency is diagnostic of this disor over the course of type 1 diabetes. Continuing insulin, even at
der. Treatment should not be withheld while awaiting further low doses, is recommended during the "honeymoon" phase
diagnostic testing since adrenal insufficiency is a potentially in order to preserve beta cell function as long as possible
life-threatening condition that may result in hemodynamic by reducing the metabolic stress on these cells. The low
instability. Treatment of primary adrenal failure requires both dose insulin regimen can consist of a basal and prandial
glucocorticoid and mineralocorticoid replacement. Hydrocor insulin combination or a basal insulin regimen. She is expe
tisone or another long-acting agent with primarily glucocor riencing symptomatic postprandial and fasting hypoglyce
ticoid activity should be given along with a mineralocorticoid mia. Decreasing the insulin aspart and insulin glargine doses
agent such as fludrocortisone. would address the prandial and fasting hypoglycemia, while
The synthetic ACTH (cosyntropin) stimulation test is also still providing low-dose insulin to protect the function
extremely sensitive for detecting either primary or second ing beta cells. She will require close monitoring of her blood
ary adrenal insufficiency. In patients with nondiagnostic glucose levels to determine when insulin doses should be
basal cortisol values (4-12 µg/dL [110.4-331.2 nmol!L]), stim increased as she nears the end of the "honeymoon" phase. The
ulation testing with synthetic ACTH is indicated. A normal "honeymoon" period may persist for several weeks to months.
response is a peak serum cortisol greater than 20 µg/dL Meal-time insulin doses are generally reduced by 50%
(552 nmol/L). ACTH stimulation testing is not needed if the when pramlintide is initiated due to the risk of hypoglycemia.
134
Answers and Critiques
The addition of pramlintide would likely exacerbate the cur commonly demonstrate oligoasthenosperrnia (reduced sperm
rent issue of hypoglycemia even with reduction of meal-time motility) and at times complete azoospermia. Three months
insulin. of treatment are typically needed prior to return of improved
The use of sliding-scale insulin without basal insulin semen parameters. Prolactin is secreted by the pituitary lac
is discouraged. When sliding-scale insulin is used without totroph cells under tonic inhibition by dopamine. Dopamine
basal insulin, the likelihood of wide swings from hypergly agonist therapy can normalize prolactin levels, reverse hypo
cemia to hypoglycemia increases. Without a basal insulin gonadism, and shrink tumors by at least 50% in almost 90%
regimen, she may not consistently receive daily insulin to of patients. Evaluation of the infertile male with abnormal
decrease the metabolic stress on her functioning pancreatic findings on semen analysis should always include investi
beta cells. gation of the hypothalamic-pituitary-testicular (HPT) axis.
Discontinuation of both insulin glargine and insulin Disturbances in this axis may result in failure of gonadotropin
aspart increases metabolic stress on the pancreatic beta cells release from the ante1ior pituitary and insufficient testosterone
and accelerates the loss of functional cells producing insulin. production as well as absent or diminished spermatogenesis.
As pancreatic beta cell function declines toward the end of Clomiphene citrate is effective only when the HPT axis
the "honeymoon" phase, the risk of diabetic ketoacidosis is intact, which does not apply for this patient. Although
increases without any exogenous insulin. the indication for clomiphene citrate in the infertile male
population remains controversial, some clinicians use it
KEY POINT
to increase endogenous follicle-stimulating hormone and
• Continuing insulin, even at low doses, is recom luteinizing hormone output from the anterior pituitary to
mended during the "honeymoon phase" of type 1 dia support testosterone production by Leydig cells.
betes mellitus to reduce metabolic stress on function Sildenafil may improve erectile dysfunction in this
ing beta cells and preserve any residual function for patient, but it will not increase endogenous testosterone
as long as possible. levels and will not improve his hyperprolactinemic state.
Testosterone replacement therapy would be helpful to
Bibliography alleviate the sexual side effects of this patient's hyperpro
DeWitt DE, Hirsch 113. Outpatient insulin therapy in type land type 2 diabe lactinemic state; however, no restoration of spermatogenesis
tes mellitus: scientific review. JAMA. 2003 May 7;289(17):2254-64. [PMID: would occur, and therefore infertility would persist. Neither
12734137]
testosterone replacement nor sildenafil therapy will reduce
the size of the patient's prolactinoma.
Item 84 Answer: A
KEY POINT
Educational Objective: Treat hypogonadism second
• Secondary hypogonadism in a male patient caused by
ary to hyperprolactinemia in a male patient.
hyperprolactinemia as a result of a prolactinoma is a
TI1e most appropriate treatment is a dopamine agonist such as possible cause of erectile dysfunction and should be
cabergoline. Hyperprolactinemia as a result of a prolactinoma treated with a dopamine agonist such as cabergoline.
is a possible cause of erectile dysfunction and decreased libido
and may be successfully treated with a dopamine agonist. In Bibliography
addition to the sexual dysfunction associated with hyperpro Mann WA. Treatment for prolactinomas and hyperprolactinaemia: a lifetime
lactinemia, semen parameters are often abnormal; patients approach. Eur J Clin Invest. 2011 Mar:41(3):334-42. [PMID: 20955213]
135
Index
Note: Page numbers followed by fand t denote figures and tables. respectively. Test Antiresorptive therapy, in Paget disease of bone, 71, Q40
questions are indicated by Q. Antithyroid drugs, in Graves disease, 44
Apathetic hyperthyroidism,42
A Asherman syndrome (AS},54, Q68
Abdominal CT scan, for androgen-producing adrenal tumor, Atenolol, in thyrotoxicosis, 43
Q52 Atherosclerotic cardiovascular disease (ASCVD}, 16
Acarbose, for diabetes mellitus, St, lOt Autoimmune adrenalitis, and primary adrenal failure, 36
ACE inhibitor, in diabetic nephropathy, 17 Autoimmune-mediated type 1 diabetes mellitus,1, 3
Acquired type 1 diabetes, 3 Autonomic neuropathy, 18
Acromegaly, 27
causes of, 27 B
clinical features and diagnosis in, 27 Bariatric surgery, 8, Q49
transsphenoidal surgery l'or, Q61 �-adrenoceptors blockers, for pheochromocytomas, 33-34
treatment of, 27-28 �-blockers
ACTH stimulation test, 22, 23 in thyroid storm treatment, 49
Adenoma in thyrotoxicosis. 43, QlO
adrenal, 32 Biguanides, for diabetes mellitus, lOt
pituitary,20 (see also Pituitary tumors} Bilateral adrenal hemorrhage, Q42
thyroid, toxic, 44 Bisphosphonates
Adrenal crisis, 36 in hypercalcemia,64, 65
Adrenal failure, bilateral adrenal hemorrhage and, Q42 in osteoporosis, 68-69
Adrenal fatigue, 38 Bone mineral density (BMD), 66-67. Ql2
Adrenal gland, disorders of, 29-40 decline in,67
adrenal hormone excess and, 30-36 and fracture risk, 67
adrenal insufficiency and,36-39 increase in. 66
adrenal masses, 39-40 measurement of,67, 681
related anatomy and physiology, 29, 291' Bromocriptine, for prolactinomas, 26
Adrenal insufficiency,36
during critical illness, 38-39 C
primary adrenal failure, 36-38 Cabergoline, Q84
Adrenal masses, 39-40 for Cushing disease,28
imaging characteristics of, 32t for prolactinomas, 26, Q19
incidentally noted, 39-40, 39f, QSO, Q60 Calcitonin, 42
Adrenal metastases, 39 for osteoporosis, 69
Adrenal vein sampling (AVS), 34 Calcitriol,62, 66
Adrenocortical carcinomas (ACCs), 32,32t, 39. 40 Calcium
surgical excision of,Q27 homeostasis and bone physiology, 61-62
Adrenocorticotropic hormone (ACTH), 19, J9t postsurgical hypoparathyroidism and supplementation intake,
and cortisol production, 29 Q34
deficiency of, 22-23, 23t Calcium carbonate, in hypocalcemia, 66
Aging male, androgen deficiency in, 57-58 Calcium citrate, in hypocalcemia, 66
Aldosterone, 29 Calcium-creatinine clearance ratio, 64-65
Aldosterone-producing adrenocortical adenomas, 34 Canagliflozin, for diabetes mellitus, 101
Alendronate Capsaicin cream, 18
for osteoporosis, 69, Q78 Cardiovascular disease (CVD}, diabetes mellitus and. 16-17,
for Paget disease of bone, 71 161
Alogliptin,for diabetes mellitus, IOt Catecholamines, 29, 29f
a-adrenoceptors blockers, for pheochromocytomas, 33 Celiac disease,autoimmune-mediated type l diabetes and, 3
a-glucosidase inhibitors, for type 2 diabetes. 4, St, lOt Central diabetes insipidus, 24-25
Amenorrhea, 54-55 Central hyperthyroidism, 45
evaluation of, 55 Central hypothyroidism,measurement of serum free thyroxine (T,,} level
primary, 54,Q9 in,Q36
secondary, 54-55 Chlorpropamide, for diabetes mellitus, IOt
American Diabetes Association (ADA), on screening for type 2 diabetes. Clomiphene citrate, 57, Q64
I, 2t Continuous glucose monitoring (CGM}, 7, Q53
Amiloride, in primary hyperaldosteronism,35 Continuous subcutaneous insulin infusion (CSII} therapy, 7-9
Amiodarone-induced thyrotoxicosis (AIT), 46 Corticotrophin-releasing hormone (CRH}, 19, 28
type l, 46 Cortisol,29
type 2, 46 Critical illness, adrenal function during, 38-39
Amitriptyline, in distal symmetric polyneuropathy, 18 Cushing disease, 28-29
Amylinomimetics, for diabetes mellitus, lOt Cushing syndrome (CS}, 28, 30-32
Anabolic steroid abuse, in men, 60 causes of, 30, 30t
Androgen abuse, in women, 56 clinical manifestations of'. 30,30f, 3lt
Androgen deficiency, in aging male, 57-58 CT of adrenal glands in, Q5
Androgen-producing adrenal tumors, 36, Q52 diagnosis of, 30-32, 31f,Q5, Q48
Angiotensin receptor blocker (ARB), in diabetic nephropathy,17 endogenous, 30
Anticonvulsants,in distal symmetric polyneuropathy, 18 iatrogenic, 30, Q23
Antidepressants, in distal symmetric polyneuropathy,18 imaging studies in, 32,321
Antidiuretic hormone (ADH}, 19 and pseudo-Cushing syndrome, 30
deficiency of, 24-25 treatment of, 32
excess of, 28 Cystic fibrosis, and infertility, QSI
137
Index
138
Index
K 0
Kallmann syndrome, and GnRH deficiency, 24 Oral glucose tolerance test (OGTT), I. 2t
Karyotype testing, Q58 Orlistat, for prevention/delay of type 2 diabetes. St
139
Index
140
Index
141