Endocrine

MKSAP 19 board
basics

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Diabetes Mellitus
Type 1 Diabetes Mellitus
Diagnosis

Type 1 diabetes is characterized by a β-cell destructive process that may eventually lead
to absolute insulin deficiency. The onset of type 1 diabetes is typically abrupt and severe
and may be associated with a precipitating event, such as infection, pregnancy,
or MI. Look for fatigue, polyuria, polydipsia, blurring of vision, weight loss, and
dehydration.

More than 90% of cases of type 1 diabetes are autoimmune (type 1A). Measuring
antibodies to GAD65 and IA-2 is recommended for initial confirmation. Approximately
20% of patients with type 1 diabetes develop other organ-specific autoimmune diseases,
such as celiac disease, Graves disease, hypothyroidism, Addison disease, pernicious
anemia, and vitiligo.

Treatment

Patients with type 1 diabetes are treated with intensive insulin therapy, which includes
intermediate-acting or long-acting insulin for basal coverage and preprandial analogue or
regular insulin injections throughout the day. Intensive insulin therapy can also include
continuous subcutaneous insulin infusion with an insulin pump and meal-time boluses.

Basal insulin dose accounts for 50% of the total daily dose of insulin; the remaining
insulin is divided to cover the preprandial doses. Examples of basal insulin options:

• Insulin glargine, insulin detemir, or insulin degludec: A single 10 PM dose

controls nocturnal plasma glucose levels and glucose levels between meals. It also
counters the early morning rise in glucose level (“dawn phenomenon”) caused by
hepatic gluconeogenesis.
• Isophane (NPH) intermediate-acting insulin: This insulin can be used in the
morning and evening to provide basal plasma insulin levels and to suppress
hepatic gluconeogenesis.

Examples of short-acting preprandial insulin options:

• Insulin aspart, insulin glulisine, and insulin lispro: rapid-acting insulin given 5 to
15 minutes before meals to modulate the postprandial rise in glucose level.
• Regular insulin: given 30 minutes before meals to prevent postprandial elevations
in blood glucose.

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Correctional insulin is the use of additional analogue or regular insulin beyond the usual
dose to treat preprandial glucose that is not at target. For example, a correction for type 1
diabetes may be an additional 1 U of insulin for every 50 mg/dL that the glucose level is
above the preprandial target.

Insulin pumps: Subcutaneous infusion of rapid-acting insulin is delivered continuously

for basal insulin requirements and given in intermittent boluses for prandial needs.

Study Table: Adjusting Insulin Dose in Diabetes Mellitus

Condition Cause
Fasting Not enough basal insulin
hyperglycemia
Prelunch Not enough rapid-acting insulin at breakfast or not enough morning
hyperglycemia NPH insulin
Predinner Not enough rapid-acting insulin at lunch or not enough morning
hyperglycemia NPH insulin
Bedtime Not enough rapid-acting insulin at dinner
hyperglycemia
Fasting or Too much basal insulin
nocturnal
hypoglycemia
Prelunch Too much rapid-acting insulin at breakfast or too much morning
hypoglycemia NPH insulin
Predinner or Too much rapid-acting insulin at lunch or dinner or too much
bedtime morning NPH
hypoglycemia

Hypoglycemia unawareness describes the presence of severely low plasma glucose levels
that occur without warning symptoms followed by sudden loss or impairment of
consciousness. Treat immediately with rapid-acting carbohydrates or a glucagon injection
followed by food. Lowering the insulin dose and allowing the average plasma glucose
level to increase for several weeks may restore sensitivity to hypoglycemia.

Type 2 Diabetes Mellitus

Diagnosis

Type 2 diabetes is characterized by a combination of insulin resistance and a β-cell

secretory defect. With time, progressive β-cell dysfunction can develop, leading to
absolute insulin deficiency.

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Because symptoms may be subtle, the time to diagnosis may be delayed. Consequently,
approximately 20% of patients with type 2 diabetes have microvascular complications of
the disease at presentation; an even higher percentage may have CAD or peripheral
vascular disease. Most patients with type 2 diabetes are obese or at least have abdominal
obesity. Characteristic findings of long-standing diabetes include:

• polyuria, polyphagia, and polydipsia

• retinal microaneurysms, dot-and-blot hemorrhages, macular edema
• symmetric sensory “stocking-glove” peripheral neuropathy
• cardiovascular and kidney disease

Screening for Type 2 Diabetes

The USPSTF recommends screening for abnormal blood glucose as part of

cardiovascular risk assessment in adults aged 35 to 70 years who are overweight or
obese.

The ADA recommends screening overweight adults (BMI ≥25; ≥23 in Asian Americans)
with at least one additional risk factor and all patients >45 years. Additional risk factors
include:

• first-degree relative with diabetes

• high-risk race/ethnicity (Black, Hispanic/Latino, American Indian, Asian, Native
Hawaiian/Pacific Islander)
• history of gestational diabetes mellitus
• history of CVD
• physical inactivity
• hypertension
• HDL cholesterol level <35 mg/dL and/or triglyceride level >250 mg/dL
• PCOS
• prediabetes on previous testing

Screen using the following tests: fasting plasma glucose, 2-hour postprandial glucose
during an OGTT, or hemoglobin A1c. If two separate tests are done simultaneously and
both are abnormal, diagnose diabetes. If only one of the two tests is abnormal, repeat the
abnormal test.

Don't Be Tricked
• A random plasma glucose level ≥200 mg/dL with hyperglycemic symptoms is
diagnostic of diabetes and does not warrant repeat measurement.

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Study Table: Diagnosis and Classification of Type 2 Diabetes Mellitus

2-Hour
Glucose
Fasting Random during
Diagnosis GlucoseGlucose OGTT Hemoglobin A1c
Increased 100-125 140-199 140-199 5.7%-6.4%
risk for mg/dL mg/dL mg/dL
diabetes
(prediabetes)
Diabetes ≥126 ≥200 ≥200 ≥6.5%
mg/dL mg/dL mg/dL
with
symptoms

Treatment

Intensive lifestyle modification (diet, exercise, weight loss) is appropriate for all
patients with prediabetes or type 2 diabetes.

Medication, such as metformin, reduces the risk of diabetes in patients with prediabetes,
although not as effectively as lifestyle interventions.

Bariatric procedures should be considered in patients with obesity.

Blood glucose monitoring includes self-monitoring of blood glucose, hemoglobin A1c, or

continuous glucose monitoring.

• Use self-monitoring of blood glucose for patients taking multiple daily injection
insulin therapy or continuous subcutaneous insulin infusion therapy.
• Obtain postprandial blood glucose levels in patients with at-goal preprandial
readings but with hemoglobin A1c not at goal.
• Obtain overnight blood glucose monitoring to detect hypoglycemia or dawn
phenomenon.

Although guidelines vary, a reasonable individualized goal for most patients is a

hemoglobin A1c of 7% to 8%. Goals are adjusted based on patient age and health status.

Don't Be Tricked
• If a patient is nonadherent with multiple insulin injections, adherence is unlikely
to increase because a pump is prescribed.
• Hemoglobin A1c will be falsely low in patients with hemolytic anemia, patients
taking erythropoietin, or patients with kidney injury.

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Pharmacologic Therapy for Type 2 Diabetes Mellitus

• Metformin is the recommended first-line oral agent for newly diagnosed type 2
diabetes.
• Hemoglobin A1c should be assessed every 3 months with adjustments to therapy
until the glycemic target is achieved and every 6 months if at goal.
• If not at goal, next preferred therapy is an SGLT2 inhibitor or a glucagon-like
peptide 1 (GLP-1) receptor agonist for patients at risk for or with
established ASCVD or with established kidney disease, and an SGLT2 inhibitor
for HF.
• In most patients who need the greater glucose-lowering effect of an injectable
medication, GLP-1 receptor agonists are preferred to insulin.
• If weight loss is a desired effect, GLP-1 receptor agonists and SGLT2 inhibitors
are the best choices.

Study Table: Pharmacologic Agents Used to Lower Blood Glucose Levels in Type 2
Diabetes Mellitus

Drug WeightASCVD HF Kidney Benefit

Metformin Neutral Possible Neutral Neutral
benefit
SGLT2 inhibitors Loss Benefit Benefit Benefit (empagliflozin,
(empagliflozin, (empagliflozin, canagliflozin,
canagliflozin) canagliflozin, dapagliflozin)
dapagliflozin)
GLP-1 receptor Loss Benefit Neutral Benefit (dulaglutide,
agonists (dulaglutide, liraglutide, semaglutide)
liraglutide,
semaglutide)
DPP-4 inhibitors Neutral Neutral Possible risk, Neutral
saxagliptin
Thiazolidinediones Gain Possible Risk Neutral
benefit,
pioglitazone
Second-generation Gain Neutral Neutral Neutral
sulfonylureas
Insulin Gain Neutral Neutral Neutral

Screening recommendations for chronic complications of diabetes: Patients with type

1 and type 2 diabetes should be screened regularly for diabetic complications, including:

• retinopathy (comprehensive eye examination)

• nephropathy (albumin-to-creatinine ratio)

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 • neuropathy (10 g monofilament, 128-Hz tuning fork, pedal pulses, and ankle
reflex)
• CVD (BP and fasting lipid profile measurements)

Screening for complications in patients with type 1 diabetes should begin at 5 years after
diagnosis and should be performed annually thereafter. Screening for complications in
patients with type 2 diabetes should begin at the time of diagnosis and be performed
annually thereafter.

Study Table: Treatment of Diabetes Complications

Condition Goal or Indication Treatment

Hypertension BP goal <130/80 mm Hg All first-line antihypertensive drug classes
(ACC/AHA hypertension
guideline)
BP goal <140/90 mm Hg ACE inhibitor or ARB in patients with
(ADA guideline) albuminuria
Diabetes and Age >40 years, diabetes, Moderate-intensity statin
average and a 10-year ASCVD
cardiovascular risk <7.5% (ACC/AHA
risk guideline)
Diabetes and CAD, peripheral vascular High-intensity statin
increased disease, or ASCVD risk
cardiovascular ≥7.5% (AHA/ACC
risk guideline)
Age 40-75 years, Moderate- to high-intensity statin
diabetes, and a calculated
10-year risk of a
cardiovascular event
≥10% (USPSTF
recommendation)
ADA and ACC/AHA SGLT2 inhibitor or GLP-1 receptor
recommendation agonist
Diabetic Urine albumin excretion ACE inhibitor or ARB, SGLT2 inhibitor,
kidney ≥30 mg/g GLP-1 receptor agonist
disease
Diabetic Proliferative and Excellent blood glucose and BP control;
retinopathy nonproliferative smoking cessation
retinopathy
Panretinal laser photocoagulation for PDR
and severe NPDR

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Study Table: Treatment of Diabetes Complications

Condition Goal or Indication Treatment

Intraocular injections of bevacizumab or
ranibizumab for severe NPDR and PDR
or macular edema
Diabetic Numbness, tingling, Amitriptyline, venlafaxine, duloxetine,
peripheral burning, heaviness, pain, paroxetine, pregabalin, gabapentin,
neuropathy or sensitivity in stocking- valproate, or capsaicin cream
glove distribution
Sexual Erectile dysfunction Oral phosphodiesterase inhibitor
dysfunction (sildenafil, vardenafil, tadalafil)
Gastroparesis Early satiety, nausea and Small feedings; metoclopramide or
vomiting erythromycin
Diabetic foot Ulcer or osteomyelitis See Infectious Disease, Diabetic Foot
Infections
• NPDR = nonproliferative diabetic retinopathy; PDR = proliferative diabetic
retinopathy.
Figure 1. Nonproliferative Diabetic Retinopathy:
Dot-and-blot hemorrhages and clusters of hard, yellowish exudates are characteristic of
nonproliferative diabetic retinopathy.

Figure 2. Proliferative Diabetic Retinopathy:

A network of new vessels (neovascularization) is shown protruding from the optic nerve.

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Don't Be Tricked
• Do not treat diabetic mononeuropathy (e.g., third nerve palsy); symptoms resolve
spontaneously.

Test Yourself
A 29-year-old woman with a 10-year history of type 1 diabetes has nocturnal
hypoglycemia. Her insulin schedule includes 24 U NPH insulin/10 U regular
insulin before breakfast and 14 U NPH insulin/10 U regular insulin before dinner.
Her hemoglobin A1c is 7.2%. What change should be made to her insulin regimen?

Answer: For management, three answers are possible: Delay the NPH insulin
until bedtime, lower the evening NPH dose, or (an even better choice) stop the
NPH insulin and substitute insulin glargine, detemir, or degludec at bedtime.

Hyperglycemic Hyperosmolar
Syndrome and Diabetic Ketoacidosis
Diagnosis
Hyperglycemic hyperosmolar syndrome (HHS) occurs with extreme hyperglycemia
(>600 mg/dL) in older patients with type 2 diabetes mellitus, no or low serum levels of
ketones, and a relatively normal arterial pH and bicarbonate level.

The major manifestations of DKA are hyperglycemia, ketosis, and hypovolemia.

Laboratory findings include a plasma glucose level ≥250 mg/dL, arterial blood pH ≤7.30,
bicarbonate level ≤15 mEq/L, increased anion gap, and positive serum ketone levels.

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Evaluate patients with either HHS or DKA for underlying precipitants such as medication
nonadherence, infection, and MI and confounding medications (atypical antipsychotics,
glucocorticoids). Euglycemic DKA can occur in patients taking SGLT2 inhibitors.

Treatment
Study Table: Management of Hyperglycemic Crisis: DKA and HHS

Insulin
Fluids (Regular) Potassium Correction of Acidosis
Assess for Give regular Assess for If pH is <6.9, consider sodium
volume status, insulin, 0.1 adequate bicarbonate, 100 mEq in 400 mL of
then give U/kg, as an kidney sterile water, and potassium chloride,
0.9% saline IV bolus, function with 20 mEq, infused over 2 hours.
IV at 1 L/h followed by adequate urine
initially in all 0.1 U/kg/h as output If pH is 6.9 or greater, do not give
patients and an IV (approximately sodium bicarbonate.
continue if infusion. 50 mL/h).
patient is
severely If plasma If serum
hypovolemic. glucose level potassium is
Switch to does not <3.3 mEq/L,
0.45% normal decrease by do not start
saline at 250- 10% in the insulin;
500 mL/h if first hour, instead, give
corrected give IV potassium
serum sodium additional chloride, 20-30
level becomes bolus of 0.14 mEq/h,
normal or U/kg and through central
high. resume line catheter
previous until serum
When plasma infusion rate. potassium
glucose level level is >3.3
reaches 200 When plasma mEq/L. Then
mg/dL in glucose level add 20-30
patients with reaches 200 mEq of
DKA or 300 mg/dL in potassium
mg/dL in DKA and chloride to
HHS in the 300 mg/dL in each liter of IV
setting of HHS, reduce fluids to keep
continued IV insulin to serum
insulin, switch 0.02-0.05 potassium
to 5% U/kg/h and

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Study Table: Management of Hyperglycemic Crisis: DKA and HHS

Insulin
Fluids (Regular) Potassium Correction of Acidosis
dextrose with maintain level in the 4-5
0.45% saline plasma mEq/L range.
at 150-250 glucose level
mL/h to avoid between 150- If serum
hypoglycemia. 200 mg/dL potassium
until anion level is >5.2
gap acidosis mEq/L, do not
is resolved in give potassium
DKA. chloride;
instead, start
Plasma insulin and IV
glucose fluids and
should be check serum
maintained potassium
between 250- level every 2
300 mg/dL in hours.
HHS until
patient is
alert and
hyperosmolar
state
resolves.

Don't Be Tricked
• DKA can present with abdominal pain.
• Reducing the insulin infusion before complete clearing of ketones will cause a
relapse of DKA.
• Treatment of severe acidosis with bicarbonate is controversial, and evidence of
benefit is lacking.

Diabetes Care for Hospitalized Patients

Treatment
Insulin is the preferred treatment for achieving inpatient glycemic control. Critically ill
patients with type 2 diabetes are treated with IV insulin infusion when plasma glucose
levels exceed 180 to 200 mg/dL. Glucose goals are 140 to 180 mg/dL.

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For non–critically ill patients who are eating, the insulin regimen should incorporate both
basal and prandial coverage. Prandial coverage can be supplemented with correction
factor insulin for preprandial hyperglycemia.

Don't Be Tricked
• Do not select sliding scale insulin alone to treat in-hospital hyperglycemia.
• Tight inpatient glycemic control (80-110 mg/dL [4.4-6.1 mmol/L]) is not
consistently associated with improved outcomes and may increase mortality.

Continuing outpatient oral or noninsulin injectable agents is not recommended when

patients are hospitalized because of the potential for hemodynamic or nutritional changes.
Continuing oral agents should be considered only in a stable inpatient with glycemic
control at goal who has no anticipated changes in nutrition or hemodynamic status.

Pregnancy and Diabetes

Screening
Screen select women with risk factors for diabetes at the beginning of gestation. Screen
all women for gestational diabetes at 24 to 28 weeks of gestation (ADA) or after 28
weeks (USPSTF) with the 75-gram 2-hour OGTT.

Don't Be Tricked
• Women with a history of gestational diabetes are at very high risk for developing
type 2 diabetes and require annual screening following delivery.

Treatment
Glycemic targets in pregnancy include premeal plasma glucose <95 mg/dL, 1-hour
postprandial values <140 mg/dL, and 2-hour postprandial values <120 mg/dL.

Try lifestyle interventions as initial treatment, with the addition of insulin if glycemic
targets are not met.

Management strategies in pregnant women with diabetes are different from those in other
patients with diabetes:

• Insulin should replace oral hypoglycemic agents.

• ACE inhibitors, ARBs, and cholesterol-lowering drugs should be stopped before
pregnancy.

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 • A comprehensive eye examination should be completed once per trimester.

Employ aggressive BP control to avoid worsening of diabetic nephropathy and

retinopathy. Antihypertensive agents that can be safely used during pregnancy include
methyldopa, β-blockers (except atenolol), calcium channel blockers, and hydralazine.

Hypoglycemia in Patients Without

Diabetes
Diagnosis
Evaluate for hypoglycemia if the criteria for Whipple triad are met: neuroglycopenic
symptoms, hypoglycemia ≤55 mg/dL, and resolution of symptoms with glucose
ingestion.

Hypoglycemic disorders are classified as postprandial or fasting.

Postprandial hypoglycemia typically occurs within 5 hours of the last meal and is
commonly caused by previous gastrectomy or gastric bypass surgery.

Study Table: Diagnosis of Nondiabetic Fasting Hypoglycemia

Condition Diagnosis
Surreptitious Patient has access to hypoglycemic agents. Serum C-peptide levels
use of oral are inappropriately elevated at time of hypoglycemia. Perform urine
hypoglycemic screen for sulfonylurea and meglitinide metabolites.
agents
Surreptitious Patient has access to insulin. Serum C-peptide levels are low at time
use of insulin of hypoglycemia.
Insulinoma Perform 72-hour fast and document fasting plasma glucose level
<45 mg/dL, serum insulin >5-6 mU/L, and elevated C-peptide
levels. If positive, schedule abdominal CT.
Substrate Starvation, liver failure, or sepsis; suppressed hepatic glucose
deficiency production (alcoholism; cortisol or GH deficiencies)

Begin the evaluation of all patients with fasting hypoglycemia with screening for
surreptitious use of an oral hypoglycemia agent, such as a sulfonylurea or insulin.

MEN1 can present as hyperparathyroidism, pituitary neoplasms, or

pancreatic NETs. Pancreatic NETs include gastrinomas that can cause PUD and
insulinomas that can cause hypoglycemia.

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Don't Be Tricked
• Do not use home glucometers to document hypoglycemia, because they may be
inaccurate.
• Asymptomatic hypoglycemia with a plasma glucose level <60 mg/dL is often
found after fasting in patients without underlying disease and does not require
evaluation.

Treatment
Treat acute hypoglycemia with oral carbohydrates, IV glucose, or glucagon.

For management of postprandial hypoglycemia associated with previous gastrectomy or

gastric bypass surgery, choose small mixed meals containing protein, fat, and high-fiber
complex carbohydrates.

Test Yourself
A previously healthy 28-year-old female registered nurse is found unconscious on
the ward where she works. Her plasma glucose level is 28 mg/dL. She regains
consciousness following IV glucose administration. Serum insulin level is 42
mU/L (normal, 2-20 mU/L), and serum C-peptide level is 7.2 ng/mL (normal, 0.9-
4.0 ng/mL).

Answer: For diagnosis, select factitious hypoglycemia. For management, choose

screening for surreptitious ingestion of hypoglycemic agents such as
sulfonylureas.

Pituitary Hormone Deficiency

Diagnosis
Panhypopituitarism is a condition in which adequate production of all anterior pituitary
hormones is lacking, usually because of a large tumor (see Pituitary Adenomas
following), apoplexy, necrosis, autoimmune disorder, or complications of pituitary
surgery.

Pituitary apoplexy results from sudden pituitary hemorrhage or infarction and is often
associated with sudden headache, visual change, ophthalmoplegia, and altered mental
status.

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Postpartum pituitary necrosis (Sheehan syndrome) is caused by silent pituitary
infarction; is usually associated with obstetric hemorrhage and hypotension; and most
commonly presents with amenorrhea, a postpartum inability to lactate, and fatigue.

Lymphocytic hypophysitis causes hypopituitarism and, possibly, symptoms of a mass

lesion. Most cases of lymphocytic hypophysitis occur during or after pregnancy but may
be the result of cancer immunotherapy with checkpoint inhibitors.

The posterior pituitary releases vasopressin and oxytocin directly into the systemic
circulation. Deficiencies of these hormones can occur independent of anterior pituitary
dysfunction.

Look for symptoms of panhypopituitarism:

• fatigue, nausea, vomiting, weight loss, or abdominal pain (ACTH deficiency)

• cold intolerance, weight gain, or constipation (TSH deficiency)
• visual field diagram showing bitemporal loss of vision (mass effect on the optic
chiasm)
• amenorrhea, loss of libido, or erectile dysfunction (FSH/LH deficiency)
• loss of muscle mass (GH deficiency)

Look for symptoms of posterior pituitary dysfunction:

• polydipsia, polyuria, and nocturia (DI secondary to ADH deficiency)

Testing
Pituitary hormone deficiency is confirmed by documenting target-organ hormone
deficiency and a corresponding low or “normal” serum pituitary hormone level.
Stimulation testing may be needed to document hypopituitarism.

Study Table: Key Hormone Tests for Pituitary Hormone Deficiency

Pituitary Peripheral Initial

HormoneHormone Test(s) Confirmatory Test
ACTH Cortisol Simultaneous ACTH stimulation test
8 AM ACTH,
cortisol
LH and Testosterone or Simultaneous
FSH estradiol LH, FSH,
8 AM total
testosterone
(male),

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Study Table: Key Hormone Tests for Pituitary Hormone Deficiency

Pituitary Peripheral Initial

HormoneHormone Test(s) Confirmatory Test
estradiol
(female)
TSH Thyroxine, Simultaneous
triiodothyronine TSH, free (or
total)
thyroxine
GH IGF-1 IGF-1 GHRH-arginine

Insulin tolerance

Glucagon stimulation

Ghrelin agonist stimulation

• GHRH = growth hormone releasing hormone.

After documenting pituitary hormone deficiency, select dedicated pituitary MRI.

Don't Be Tricked
• It is not necessary to measure serum FSH/LH levels in women who have normal
menstrual cycles.

Treatment
Patients with panhypopituitarism require daily thyroxine and cortisol
replacement. Androgen replacement is appropriate for men with hypogonadism, and
estrogen replacement is used for premenopausal women with hypogonadism. GH
replacement is rarely indicated.

Don't Be Tricked
• Thyroxine dosing for central hypothyroidism is based on serum free T4 rather than
TSH levels.
• T4 replacement is indicated only after hypoadrenalism has been ruled out or
treated.

Test Yourself

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A 65-year-old man was diagnosed with SCLC 20 years ago and received
chemotherapy and chest and cranial irradiation. Physical examination shows
hypotension, tachycardia, and small testes. Serum sodium is 123 mEq/L.

Answer: For diagnosis, choose hypopituitarism. For management, select

immediate replacement with stress doses of hydrocortisone followed by
confirmatory testing.

Pituitary Adenomas
Diagnosis
Pituitary adenomas are benign tumors that originate from one of the different anterior
pituitary cell types. They are classified based on size as microadenomas (<10 mm) or
macroadenomas (≥10 mm).

Pituitary adenomas become symptomatic by two different mechanisms:

• mass effect causing hypopituitarism (anterior hormone deficiencies more common

than posterior), headaches, visual disturbance/visual field defects, and cranial
nerve dysfunction
• endocrine hyperfunction caused by excess secretion by the tumor (most
commonly prolactinomas)

Figure 3. Visual Field Defects:

Bitemporal quadrant visual field defects secondary to a pituitary mass.

Don't Be Tricked
• The pituitary gland is enlarged diffusely in untreated primary hypothyroidism and
during normal pregnancies.

Testing
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Most incidentally noted pituitary masses in asymptomatic patients are benign,
nonfunctional pituitary adenomas.

• Obtain dedicated pituitary MRI.

• Assess possible pituitary hypersecretion (measure prolactin and IGF-1).

Screen patients for hypopituitarism with pituitary tumors regardless of symptoms with
measurement of:

• FSH, LH
• cortisol
• TSH, T4
• total testosterone (men)

Don't Be Tricked
• A menstrual history can assess for hypogonadotropic hypogonadism in
premenopausal women.
• Testing for Cushing disease is not necessary in the absence of symptoms.

Study Table: Diagnosis of Pituitary Adenomas

If you see Think

this… this… Order this…
Galactorrhea, Prolactinoma Serum prolactin level
amenorrhea
Enlargement of Acromegaly Serum IGF-1
hands, feet,
nose, lips, or OGTT (fails to suppress GH)
tongue;
increased
spacing of teeth
Proximal Cushing 24-Hour urine cortisol excretion, dexamethasone
muscle disease suppression test, or late-night salivary cortisol level
weakness, facial (elevated), serum ACTH level (elevated or
rounding, inappropriately “normal”)
centripetal
obesity, purple
striae, diabetes
mellitus, and
hypertension
Goiter and TSH- TSH normal or elevated; increased T4
hyperthyroidism secreting

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Study Table: Diagnosis of Pituitary Adenomas

If you see Think

this… this… Order this…
adenoma
(rare)
Figure 4. Prolactinoma:
A discrete area of hypolucency (arrow) is seen in an otherwise normal-sized pituitary
gland of homogeneous density.

Don't Be Tricked
• Psychotropic agents, tricyclic antidepressants, antiseizure medications,
metoclopramide and domperidone, calcium channel blockers, methyldopa,
opioids, and protease inhibitors can cause hyperprolactinemia.
• The prolactin level influenced by drugs and other nonprolactinoma conditions is
usually <150 ng/mL.
• Obtain a pregnancy test in all women with hyperprolactinemia.
• Obtain a serum TSH level in all patients with hyperprolactinemia
(hypothyroidism can cause hyperprolactinemia).

Treatment
Choose observation for women with microprolactinoma and normal menses or for
patients with nonfunctioning pituitary microadenomas.

Choose a dopamine agonist (cabergoline preferred to bromocriptine) for symptomatic

prolactinoma.

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Choose surgery for adenomas secreting GH, ACTH, or TSH; for adenomas associated
with mass effect, visual field defects, or hypopituitarism; and for prolactinomas
unresponsive to dopamine agonists.

Test Yourself
A 32-year-old woman has a 4-mm hypointense area in the pituitary gland
discovered incidentally on an MRI. Medical history, including menstrual function,
and physical examination are normal. The serum prolactin level and thyroid
function tests are normal.

Answer: For diagnosis, choose an incidental nonfunctioning pituitary adenoma.

For management, repeat the MRI in 1 year.

Diabetes Insipidus
Diagnosis
DI is characterized by an inability to concentrate urine because of insufficient
arginine vasopressin (AVP, ADH) release (central DI) or activity (nephrogenic
DI).

Symptoms and signs of central DI are polydipsia; polyuria; nocturia; and,

depending on mass effect of a pituitary tumor, visual field deficits.

Testing
Measure the plasma glucose level to rule out diabetes mellitus and the serum
calcium level to rule out hypercalcemia as causes of polyuria.

An inappropriately low urine osmolality in the setting of an elevated serum

osmolality and hypernatremia in a patient with polyuria is diagnostic.

A water deprivation test can be performed when the diagnosis is uncertain.

Following water deprivation, an elevated serum osmolality or hypernatremia with
inappropriately dilute urine is diagnostic.

Evaluating the response to desmopressin can help differentiate central from

nephrogenic DI.

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If the desmopressin challenge test is positive (urine concentrates, indicating
central DI), order an MRI of the pituitary gland. If the test is negative (urine does
not concentrate, indicating nephrogenic DI), order kidney ultrasonography.

Treatment
Central DI is treated with desmopressin.

Test Yourself
A previously healthy 27-year-old woman has a 1-month history of polydipsia and
polyuria. Her plasma urine output is 4 L/d, urine osmolality is 95 mOsm/kg H2O,
and simultaneous serum osmolality is >295 mOsm/kg H2O. Serum glucose and
calcium are normal. Urine osmolality increases to >800 mOsm/kg H2O after
desmopressin.

Answer: For diagnosis, choose central DI.

Empty Sella Syndrome

Diagnosis
Empty sella is diagnosed when the normal pituitary gland is not visualized or is
excessively small on MRI. Causes include:

• increased CSF entering and enlarging the sella

• tumor
• previous pituitary surgery, radiation, or infarction

Testing
In asymptomatic persons, obtain cortisol, TSH, and free (or total) T4 measurements.

Hyperthyroidism
Diagnosis
The term thyrotoxicosis encompasses any cause of thyroid hormone
excess. Hyperthyroidism is thyrotoxicosis caused by excessive endogenous thyroid
hormone production.

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Look for symptoms of thyrotoxicosis:

• nervousness, emotional lability

• increased sweating, heat intolerance
• palpitations
• increased defecation
• weight loss
• menstrual irregularity

Look for signs of thyrotoxicosis:

• tachycardia
• lid lag
• fine tremor
• muscle wasting, proximal muscle weakness
• hyperreflexia

The most common causes of hyperthyroidism are Graves disease and toxic adenoma(s).
Physical examination findings specific for Graves disease include goiter, ophthalmopathy
(proptosis, chemosis, and extraocular muscle palsy), and pretibial myxedema.

Older adult patients with hyperthyroidism may present with depression, AF, and HF.

Thyrotoxicosis occurs in destructive thyroiditis because thyroid damage results in release

of preformed thyroid hormone into the circulation.

Thyroid storm is the development of life-threatening hyperthyroidism associated with

cardiac decompensation, fever, delirium, and psychosis. It may occur following surgery,
infection, or administration of an acute iodine load (contrast agents) and may also
develop in patients with untreated Graves disease. Thyroid storm is a clinical diagnosis;
no level of thyroid hormone elevation is diagnostic.

Testing
Order serum TSH and free T4 levels to make the diagnosis of thyrotoxicosis. If TSH is
suppressed but T4 is normal, order free T3 to diagnose T3 toxicosis (rare).

Thyroglobulin levels can be elevated in hyperthyroidism and thyroiditis. Intake of

exogenous thyroid hormone suppresses thyroglobulin levels, which makes its
measurement useful (when low) in patients with thyrotoxicosis caused by surreptitious
use of thyroid hormone.

An elevated serum ESR supports thyroiditis, whereas TSH-receptor antibodies and

thyroid-stimulating immunoglobulins are associated with Graves disease. However,

22
antibodies need not be checked routinely in the evaluation of hyperthyroidism unless the
diagnosis is unclear.

Study Table: Interpreting Thyroid Function Tests in Hyperthyroidism

If you see
this… Choose this…
↓ TSH, ↑ Primary hyperthyroidism
free T4
↓ TSH, ↑ Primary hyperthyroidism with T3 toxicosis
T3,
normal
free T4
↓ TSH, Subclinical hyperthyroidism
normal
T3 and
free T4,
without
symptoms
↑ TSH, ↑ Secondary hyperthyroidism from a pituitary tumor (central
T3, ↑ free hyperthyroidism, very rare)
T4

Imaging
Study Table: Radioactive Iodine Uptake and Scan Interpretation

Result Diagnosis
Diffuse Graves disease
homogeneous
increased
uptake
Patchy areas Toxic multinodular goiter
of increased
uptake
Focal Solitary adenoma
increased
uptake with
decreased
uptake in the
rest of the
gland

23
Study Table: Radioactive Iodine Uptake and Scan Interpretation

Result Diagnosis
Decreased or Iodine load (IV contrast or amiodarone)
no uptake
Thyroiditis (silent, subacute, postpartum, or amiodarone induced)

Surreptitious ingestion of excessive thyroid hormone

Treatment
Most patients with thyrotoxicosis benefit from β-blockers to reduce adrenergic symptoms
rapidly. Available treatment strategies for hyperthyroidism include antithyroid drugs,
radioactive iodine therapy (131I), and thyroid surgery.

Radioactive iodine

• toxic multinodular goiter

• toxic adenoma
• Graves disease (usually following failed drug therapy)

Radioactive iodine is not used during pregnancy or breastfeeding and may aggravate
Graves ophthalmopathy.

Moderate to severe Graves ophthalmopathy may require treatment with glucocorticoids,

surgery, or teprotumumab.

Antithyroid drugs may lead to a drug-free remission of Graves disease in up to 50% of

patients after 2 years of treatment.

Study Table: Comparison of Antithyroid Drugs

Indicated
Treatment for… Watch for…
Methimazole First-line Agranulocytosis, drug rash, hepatotoxicity
antithyroid
medication
for most
patients
Propylthiouracil Treatment of Same as methimazole except more frequent
choice in first hepatotoxicity
trimester of
pregnancy;
preferred in

24
Study Table: Comparison of Antithyroid Drugs

Indicated
Treatment for… Watch for…
thyroid storm
(inhibits
peripheral T4-
T3 conversion)

Thyroidectomy is preferred as definitive therapy for hyperthyroidism:

• large goiter with compressive symptoms

• intolerance to other therapies

Subclinical hyperthyroidism is diagnosed by TSH suppression with normal T4 and

T3 levels. Treatment is recommended for TSH <0.1 μU/L and patients with symptoms.

Study Table: Management of Thyrotoxicosis

If you see
this… Choose this…
Sympathetic Atenolol or propranolol
nervous system
symptoms
Severe Graves Methimazole or thyroidectomy
ophthalmopathy
Avoid radioactive iodine (may cause worsening of
ophthalmopathy unless pretreated with glucocorticoids)
Pregnancy Propylthiouracil in first trimester of pregnancy; methimazole
thereafter

Radioactive iodine is contraindicated

Subclinical Methimazole if TSH <0.1 μU/mL
hyperthyroidism
Subacute NSAIDs or glucocorticoids for pain management, atenolol or
thyroiditis propranolol for symptoms of hyperthyroidism, levothyroxine for
symptomatic hypothyroidism, and periodic thyroid studies. In
50% of patients, thyroid studies will normalize without
intervention.
Thyroid storm Propylthiouracil (preferred) or methimazole, iodine-potassium
solutions, glucocorticoids, and β-blockers

Don't Be Tricked

25
 • A fever or sore throat in a patient taking methimazole or propylthiouracil should
be presumed to be agranulocytosis until proven otherwise.

Test Yourself
An asymptomatic 78-year-old woman has a serum TSH level of 0.2 μU/mL. Serum T3 and
T4 levels are normal.

Answer: For diagnosis, choose subclinical hyperthyroidism. For management, choose to repeat
thyroid tests in 4 to 6 months.

Hypothyroidism
Diagnosis
Symptoms and Signs

Look for symptoms suggesting hypothyroidism:

• weakness, lethargy, fatigue

• depression, impaired concentration
• myalgia
• cold intolerance
• constipation
• weight gain
• menstrual irregularity or menorrhagia
• carpal tunnel syndrome

Look for signs suggesting hypothyroidism:

• bradycardia
• hypothermia
• goiter
• cool dry skin
• delayed deep tendon reflex relaxation phase
• myopathy

Causes

26
The most common causes of hypothyroidism include:

• chronic lymphocytic (Hashimoto) thyroiditis

• thyroidectomy
• previous radioactive iodine ablation
• history of external beam radiation to the neck

Transient mild hypothyroidism typically occurs during the second phase

of destructive thyroiditis (initial phase is hyperthyroidism). Permanent
hypothyroidism may follow either postpartum thyroiditis (more common) or
subacute thyroiditis (less common).

Medication-induced hypothyroidism can occur with the use of certain drugs,

including lithium carbonate, interferon alfa, interleukin-2, and amiodarone.

Central hypothyroidism results from pituitary disease or from previous surgery

or radiation therapy to the sella. TSH and free T4 are suppressed.

Testing
Order TSH and free T4 to make the diagnosis. Measurement of T3 levels is
generally not necessary. An antithyroid peroxidase antibody assay is associated
with Hashimoto thyroiditis but is not needed to make the diagnosis; high levels are
associated with an increased risk of permanent hypothyroidism.

Hypothyroidism may be associated with hyperprolactinemia; hyponatremia; and

increased CK, AST, and cholesterol levels.

Nonthyroidal illness syndrome occurs in patients who are acutely ill with a
nonthyroidal illness. Testing reveals low or normal free T4 and suppressed TSH
(initially), followed by elevated TSH (recovery phase). Normalization of thyroid
function tests occurs 4 to 8 weeks after recovery.

Don't Be Tricked
• Thyroid scan and radioactive iodine uptake tests are not used to make the
diagnosis of hypothyroidism.

27
Study Table: Interpreting Thyroid Function Tests in Hypothyroidism
If you
see
this… Choose this…
↑ Primary hypothyroidism
TSH,
↓ free
T4
↑ Subclinical hypothyroidism
TSH,
normal
T4
↓ Secondary (central) hypothyroidism; consider hypopituitarism
TSH,
↓ free
T4

Treatment
Levothyroxine is used to treat hypothyroidism. Treatment of subclinical
hypothyroidism is controversial. Most guidelines support these treatment
indications for subclinical hypothyroidism (TSH >10 μU/mL):

• symptomatic
• pregnant or planning to become pregnant
• possibly age <30 years

Levothyroxine should be taken on an empty stomach 60 minutes before

consuming breakfast or coffee. Recall that celiac disease, calcium and iron
supplements, and PPIs can decrease levothyroxine absorption; medications
affecting absorption should be taken at least 4 hours apart from levothyroxine.

Don't Be Tricked

• No treatment is required for nonthyroidal illness syndrome.

• Check thyroid function tests frequently during pregnancy in women with a
known diagnosis of hypothyroidism taking thyroxine, because maternal
thyroxine demand increases by 30% to 50%.

28
Study Table: Levothyroxine Treatment of Hypothyroidism
ConditionTreatment
Age <60 Begin full-dose levothyroxine (about 100 μg/d)
years
Age >60 Begin levothyroxine at 25-50 μg/d
years
Increase by 25 μg every 6 weeks until TSH level is 1.0-2.5 μU/mL
Heart Begin levothyroxine at 12.5-25 μg/d
disease
Increase by 12.5-25 μg every 6 weeks until TSH level is 1.0-2.5 μU/mL

Thyroid Nodules
Diagnosis
Thyroid nodules are common and are often found incidentally on physical examination or
imaging tests.

Look for risk factors for thyroid cancer, including family history of thyroid malignancy,
personal history of radiation therapy to the head and neck, or other radiation exposure in
childhood.

Imaging and Testing

When a nodule is discovered, assess thyroid function with a serum TSH level.

• Low TSH → obtain radioisotope scan scintigraphy to confirm the diagnosis of

autonomously functioning thyroid adenoma and to rule out additional
nonfunctioning nodules.
• Normal or high TSH → obtain ultrasonography.

Thyroid nodule characteristics and size on ultrasound determine the need

for FNAB. FNAB is not recommended for subcentimeter nodules unless associated with
symptoms, pathologic lymphadenopathy, extrathyroidal extension, history of childhood
radiation exposure, or family thyroid cancer syndrome.

FNAB is indicated for:

• all thyroid nodules >1 cm with suspicious sonographic features and a normal TSH
level

29
 • nodules <1 cm in patients with risk factors for thyroid cancer or suspicious
ultrasound characteristics

In patients with multinodular goiter, the risk for malignancy is the same for multiple
nodules as it is for a solitary nodule; therefore, evaluation and management are identical.

Evaluate patients with multinodular goiter for compressive symptoms:

• dysphagia
• hoarseness
• dyspnea (tracheal compression from substernal goiter)

Consider evaluation with barium swallow, direct vocal cord visualization, spirometry
with flow volume loops, and/or chest CT as needed.

Figure 5. Thyroid Nodule:

A hyperfunctioning nodule is shown on the lateral aspect of the left thyroid lobe on
thyroid scan.

Don't Be Tricked
• Serum thyroglobulin measurement is not helpful in distinguishing benign from
malignant thyroid nodules.
• Calcitonin measurement is considered only in patients with hypercalcemia or a
family history of thyroid cancer or MEN2.

Treatment

30
Observation: Follow benign nodules with periodic ultrasonography. Malignancy must be
ruled out when a nodule increases in size or if a nodule develops concerning ultrasound
characteristics.

Radioactive iodine or surgery: Treat hyperfunctioning solitary thyroid nodules with

radioactive iodine ablation or hemithyroidectomy.

Surgery is indicated for patients with:

• continued nodule growth despite normal initial FNAB results

• nondiagnostic results on repeat FNAB
• malignant cytology
• large multinodular goiters with compressive symptoms

Don't Be Tricked
• Do not prescribe T4-suppression therapy for benign thyroid nodules.

Test Yourself
An 18-year-old man has a 2-cm solid right-sided thyroid nodule. The serum TSH
level is 1.4 μU/mL.

Answer: For management, choose FNAB.

Hypercortisolism (Cushing Syndrome)

Diagnosis
Cushing syndrome results from excess glucocorticoid.

The most common cause of Cushing syndrome is the use of systemic, topical, intra-
articular, or inhaled glucocorticoids. Doses of prednisone (or equivalent) >10 to 20 mg/d
can cause hypothalamic–pituitary–adrenal axis suppression after ≥3 weeks of consecutive
use.

Endogenous causes of Cushing syndrome can be ACTH dependent or independent.

ACTH-dependent causes of Cushing syndrome are defined by ACTH levels elevated or

inappropriately “normal” in relation to the cortisol level:

• ACTH-secreting pituitary adenomas (Cushing disease)

31
 • ACTH-secreting carcinomas and carcinoid tumors

ACTH-independent causes of Cushing syndrome are defined by low or “normal” ACTH

levels in relation to the cortisol level:

• adrenal adenomas
• adrenal carcinomas

Clinical findings highly specific for Cushing syndrome include:

• proximal muscle weakness

• facial plethora
• supraclavicular or dorsocervical (“buffalo hump”) fat pads
• wide (>1 cm) violaceous striae

Testing
First-line diagnostic studies include:

• 1-mg overnight dexamethasone suppression test (failure to suppress serum

cortisol to <3 μg/dL)
• 24-hour urine cortisol level (elevated)
• late night salivary cortisol level (elevated)

If the cortisol level is elevated (or not suppressible), obtain an ACTH level to
differentiate ACTH-dependent from ACTH-independent hypercortisolism.

Study Table: Evaluation of Hypercortisolism

If you see
this… Do this…
Morning Pituitary MRI or CT
ACTH
elevated
Morning Adrenal CT
ACTH
suppressed
or normal

Don't Be Tricked
• Evaluation for Cushing syndrome should be limited to patients with a significant
clinical suspicion of disease, including specific signs of Cushing syndrome or an
adrenal mass.

32
 • False-positive results (failure to suppress cortisol) with the 1-mg dexamethasone
suppression test are common owing to alcohol use, obesity, and psychological
disorders.

Treatment
Surgical resection is the definitive treatment for benign and malignant cortisol-secreting
adrenal tumors. Bisphosphonates are the treatment of choice for low bone density caused
by hypercortisolism.

Figure 6. Cushing Syndrome:

Wide purple striae characteristic of Cushing syndrome.

Test Yourself
A 43-year-old woman has diabetes mellitus; hypertension; hirsutism; and wide,
purple abdominal striae. The serum cortisol level is 26 μg/dL after administration
of 1 mg of dexamethasone. The serum ACTH level is 50 pg/mL.

Answer: For diagnosis, choose pituitary tumor. For testing, select pituitary gland
MRI.

Adrenal Incidentaloma
Diagnosis
An adrenal incidentaloma is a mass >1 cm that is discovered incidentally.

Testing

33
The two goals of evaluation are to determine if an adenoma is functioning and if it is
malignant.

Figure 7. Algorithm for the Initial Diagnostic Evaluation and Follow-up of an

Incidentally Noted Adrenal Mass:
HTN = hypertension; HU = Hounsfield units; K = potassium; LDST = low-dose (1-mg)
dexamethasone suppression test; MACE = mild autonomous cortisol excess; NFAT =
nonfunctioning adrenal tumor; PAC = plasma aldosterone concentration; PRA = plasma
renin activity.

Data from Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal incidentalomas:

a

European Society of Endocrinology clinical practice guideline in collaboration with the

European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016;175:G1-
34. PMID: 27390021 doi:10.1530/EJE-16-0467
b
Refer to Table 21 in MKSAP 19 Endocrinology and Metabolism 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.

Positive screening tests usually require further biochemical evaluation to confirm the
c

diagnosis.
d
Measure plasma metanephrines if radiographic appearance is typical for a
pheochromocytoma; otherwise measure 24-hour urine metanephrines and
catecholamines.
e
Hormonal evaluation for an androgen-producing adrenal tumor is indicated only if
clinically suspected based on the presence of hirsutism, virilization, or menstrual
irregularities in women.

34
Treatment
Surgery is recommended for adrenal masses >4 cm in diameter or functioning tumors.

35
Hypoadrenalism
Diagnosis
Adrenal insufficiency may be caused by disease of the adrenal glands (primary) or
disorders of the pituitary gland (secondary). Primary disease (Addison disease) results in
loss of cortisol, aldosterone, and adrenal androgens; secondary insufficiency causes only
cortisol and adrenal androgen deficiencies (aldosterone synthesis is
not ACTH dependent).

Symptoms and Signs

Characteristic findings include:

• weight loss
• fatigue, anorexia, nausea, vomiting, abdominal pain
• orthostatic hypotension
• hypoglycemia
• eosinophilia
• hyperpigmentation (primary adrenal insufficiency only)
• hyponatremia and hyperkalemia (primary adrenal insufficiency only)
• hypercalcemia

Causes

Autoimmune adrenalitis is the most common cause of primary insufficiency.

Glucocorticoid use is the most common cause of secondary insufficiency (hypothalamic-

pituitary suppression). Look for patients who recently discontinued glucocorticoid
therapy or did not increase their glucocorticoid dose in times of stress.

Testing
An 8:00 AM serum cortisol <3 μg/dL confirms cortisol deficiency and values >18 μg/dL
exclude the diagnosis.

For patients with unequivocally low cortisol levels, a morning ACTH level can help
distinguish between primary and secondary adrenal insufficiency.

36
Study Table: Evaluation of Hypocortisolism

If you see
this… Do this…
Morning Adrenal CT
ACTH
elevated
Morning Pituitary MRI
ACTH
suppressed
or
“normal”

For nondiagnostic cortisol values, select stimulation testing with synthetic ACTH
(cosyntropin). A stimulated serum cortisol >18 μg/dL excludes adrenal insufficiency.

Don't Be Tricked
• Approximately 50% of patients with autoimmune adrenal insufficiency have other
autoimmune endocrine disorders (thyroid disease, type 1 diabetes, vitiligo),
referred to as autoimmune polyglandular syndrome; testing for these disorders
is indicated.

Treatment
If acute adrenal insufficiency is suspected, treat empirically with high-dose (4 mg)
dexamethasone and IV saline without waiting for the ACTH and cortisol level results to
return from the laboratory. Dexamethasone does not interfere with the serum cortisol
assay.

Chronic replacement therapy:

• oral hydrocortisone 15 to 25 mg/d (standard dose)

• oral fludrocortisone (primary adrenal insufficiency)
• oral hydrocortisone 2 to 10 times standard dose during periods of physiologic
stress, including minor surgery
• IV hydrocortisone 100 mg followed by 50 mg every 6 h for major stress (major
surgery, trauma, critical illness, childbirth)
• fludrocortisone is not required in primary adrenal insufficiency if the
hydrocortisone dose >40 mg/d

Don't Be Tricked
• Do not prescribe dexamethasone for chronic replacement therapy.

37
Test Yourself
A 32-year-old man with hypothyroidism has a 3-month history of fatigue,
weakness, nausea, and a 13.9-kg (30-lb) weight loss. He has orthostatic
hypotension and increased pigment in the palmar creases. The serum sodium level
is 132 mEq/L and the serum potassium level is 5 mEq/L.

Answer: For diagnosis, choose autoimmune adrenalitis.

Pheochromocytoma
Diagnosis
Pheochromocytomas are rare tumors arising in the chromaffin cells of the adrenal
medulla that secrete biogenic amines (norepinephrine, epinephrine, or dopamine) or their
metabolites.

Symptoms and Signs

Indications for testing:

• adrenergic-type spells (headache, sweating, and tachycardia)

• incidentally discovered adrenal mass
• resistant hypertension (>140/90 mm Hg)
• hypertension with onset <20 years of age
• idiopathic cardiomyopathy
• hypertensive episode induced by anesthesia, surgery, or angiography
• familial syndromes that predispose to pheochromocytoma (see following)
• family history of pheochromocytoma or paraganglioma

Pheochromocytoma is associated with MEN2, von Hippel-Lindau disease, and

neurofibromatosis type 1.

Testing
Twenty-four–hour urine measurements of metanephrines and catecholamines or
measurement of plasma metanephrines is preferred.

Positive biochemical tests are followed by abdominal and pelvic CT with contrast.

Treatment
38
Surgery is the treatment of choice. Use phenoxybenzamine to control BP preoperatively.
Give IV normal saline to maintain intravascular volume; nitroprusside or phentolamine is
indicated for treating intraoperative hypertensive crisis.

Don't Be Tricked
• For control of hypertension in patients with pheochromocytoma, select α-
adrenergic blockers first. α-Adrenergic blockade before adequate β-adrenergic blockade
can result in severe paroxysmal hypertension.

Primary Hyperaldosteronism
Diagnosis
Primary hyperaldosteronism is caused by aldosterone-producing adrenal adenomas (40%)
or by bilateral adrenal hyperplasia. Testing indications are:

• untreated hypertension with sustained BP >150/100 mm Hg

• resistant hypertension (>140/90 mm Hg) with three-drug therapy including a
diuretic
• hypertension and an incidentally discovered adrenal mass
• hypertension associated with spontaneous or diuretic-induced hypokalemia
• hypertension in the setting of a first-degree relative with primary aldosteronism
• hypertension in the setting of family history of hypertension onset <40 years of
age

Testing
Evaluate patients using simultaneous measurements of plasma aldosterone and plasma
renin activity. In patients taking an ACE inhibitor or an ARB, a nonsuppressed plasma
renin level rules out mineralocorticoid excess.

A plasma aldosterone–plasma renin activity ratio >20, with a plasma aldosterone level
>15 ng/dL, strongly suggests primary hyperaldosteronism. The diagnosis is confirmed by
demonstrating nonsuppressibility of elevated plasma aldosterone in response to a high
salt load given intravenously or orally.

Testing can be done in patients receiving treatment with all antihypertensive agents
except spironolactone and eplerenone, both of which antagonize the aldosterone receptor.

After autonomous hyperaldosteronism is diagnosed, select CT of the adrenal glands.

Adrenal vein sampling is needed before surgery to confirm the source of aldosterone

39
secretion when imaging is unrevealing and to confirm lateralization when imaging
demonstrates an adrenal adenoma.

Don't Be Tricked
• Almost 50% of patients with hyperaldosteronism do NOT have hypokalemia.

Treatment
Spironolactone or eplerenone is the treatment of choice for adrenal hyperplasia.
Laparoscopic adrenalectomy is indicated for an aldosterone-producing adenoma.

Primary Amenorrhea
Diagnosis
Primary amenorrhea is the failure of menstruation (never occurred). Approximately 50%
of primary amenorrhea is caused by chromosomal disorders, commonly Turner
syndrome, in which part or all of an X chromosome is lost.

Testing
Most important studies:

• pregnancy test
• karyotype
• FSH, LH, TSH, prolactin level
• pelvic ultrasonograph

Secondary Amenorrhea
Diagnosis
Secondary amenorrhea is defined as absence of menses for more than 3 months in women
who previously had regular menstrual cycles or 6 months in women who have irregular
menses.

History and physical examination include:

• history of obstetric complications, which could lead to endometrial damage,

scarring, or adhesions
40
 • stress, weight loss, significant exercise, eating disorders
• newly initiated oral contraceptives, antipsychotics, or metoclopramide
• symptoms of pituitary adenoma (secondary to mass effect or hyperfunction)
• hirsutism, acne, history of PCOS

Testing
Test all women with secondary amenorrhea for pregnancy, the most common cause.

In the absence of pregnancy, assess hormonal status with estradiol, FSH, LH, TSH, and
prolactin levels.

Low estradiol and low or inappropriately normal FSH and LH indicate

hypogonadotrophic hypogonadism. Causes include:

• hypothyroidism
• hyperprolactinemia
• hypothalamic (stress, weight loss, exercise)
• pituitary (tumor, Sheehan syndrome)

A progesterone challenge test is performed in these patients.

• No bleeding following a progesterone challenge indicates low estrogen because of

hypothalamic hypogonadism; measure estradiol level to confirm.
• Bleeding following progesterone challenge indicates a normal estrogen state and
suggests possible hyperandrogenism (e.g., PCOS).

Low estradiol and elevated FSH and LH levels indicate hypergonadotrophic

hypogonadism. Consider:

• premature ovarian insufficiency (autoimmune)

• chemotherapy
• pelvic radiation

Treatment
Treat the underlying disorder. Prevent osteoporosis by choosing estrogen and
progesterone replacement until menstruation returns to normal or age ~50 years. For
hypothalamic amenorrhea, choose reduced exercise, improved nutrition, and attention to
emotional needs.

Polycystic Ovary Syndrome

41
Diagnosis
PCOS is the most common cause of hirsutism with oligomenorrhea. Symptoms normally
start at puberty or several years later and are slowly progressive. Diagnostic criteria differ
but typically include at least two (or all) of the following:

• ovulatory dysfunction (amenorrhea, oligomenorrhea, infertility) and/or polycystic

ovaries on ultrasound
• laboratory or clinical evidence of hyperandrogenism (hirsutism, acne)
• exclusion of other disorders

Testing
Patients should be screened for diabetes, dyslipidemia, obesity, hypertension,
and OSA. Serum testosterone and DHEAS should be measured in women with rapidly
progressive hirsutism or virilization.

Don't Be Tricked
• An androgen-secreting ovarian or adrenal tumor should be suspected in a woman
with acute onset of rapidly progressive hirsutism or virilization.

Treatment
Weight loss is a first-line intervention.

Choose metformin for prediabetes/diabetes.

If fertility is not desired, choose oral contraceptive for treatment of hirsutism and
regulation of menses; can add spironolactone if hirsutism remains a problem.

If fertility is desired, ovulation can be induced with clomiphene citrate or letrozole.

Test Yourself
A 27-year-old woman has had oligomenorrhea since age 14 years. She also has
acanthosis nigricans and hirsutism but no galactorrhea; she has obesity. She does
not desire pregnancy.

Answer: For diagnosis, choose PCOS. For management, choose intensive lifestyle
modification and an oral contraceptive.

42
Infertility
Diagnosis
Infertility is defined as the inability to conceive after 1 year of intercourse without
contraception in women <35 years and after 6 months in women ≥35 years.
Regular menses is correlated with regular ovulation. If oligomenorrhea is present,
evaluate like secondary amenorrhea. Consider structural abnormalities and
evaluate with pelvic ultrasonography or hysterography.

Male partner should be evaluated concurrently.

Male Hypogonadism
Diagnosis
Male hypogonadism is present when sperm or testosterone production is decreased. It can
be a primary (testicular) or secondary (typically hypothalamic-pituitary) condition.

Study Table: Clinical Features of Male Hypogonadism

Specific
Features Nonspecific Features
Decreased Decreased mood/energy
morning and
spontaneous Decreased muscle strength/bulk/stamina
erections
Poor sleep
Decreased
libido Poor concentration

Infertility

Gynecomastia

Decreased
male-pattern
hair growth

Causes and Testing

43
Testosterone deficiency is diagnosed with two 8:00 AM total testosterone levels below the
reference range.

• If the testosterone measurement is equivocal, measure free testosterone.

• If the testosterone level is low, measure LH, FSH, and prolactin levels.

Elevated LH and FSH values indicate primary testicular failure. Some common causes
include:

• Klinefelter syndrome (check karyotype)

• atrophy secondary to mumps orchitis
• autoimmune destruction
• previous chemotherapy or pelvic irradiation
• hemochromatosis

Low or normal LH and FSH levels indicate secondary hypogonadism. Important causes
include:

• sleep apnea
• hyperprolactinemia
• hypothalamic or pituitary disorders (hemochromatosis, pituitary/hypothalamic
tumor)
• use of opioids, anabolic steroids, or glucocorticoids

If secondary hypogonadism is confirmed, in addition to measuring prolactin, check iron

studies to rule out hemochromatosis and obtain an MRI to evaluate for hypothalamic or
pituitary lesions.

Men who self-administer anabolic steroids can come to medical attention because of
infertility. Physical examination typically reveals acne, muscular hypertrophy, testicular
atrophy, and gynecomastia (if the patient is using testosterone). Laboratory data show
suppressed LH and FSH levels, variable testosterone levels, and otherwise normal
pituitary function.

Don't Be Tricked
• Do not measure serum testosterone if a patient is having regular morning
erections, has no gynecomastia on examination, and has a normal genital
examination.

Treatment

44
Testosterone can be administered by multiple routes. Before initiation of testosterone
replacement and during therapy, routinely monitor hematocrit and PSA to screen for the
development of erythrocytosis and prostate cancer, respectively.

Don't Be Tricked
• Don't provide testosterone replacement therapy for nonspecific symptoms such as
fatigue and weakness in the absence of unequivocal testosterone deficiency.
• Testosterone therapy does not treat infertility (impairs spermatogenesis).

Gynecomastia
Diagnosis
Gynecomastia is caused by proliferation of glandular tissues in the male breast because of
an increase in the ratio of estrogen to androgen. Diagnosis is confirmed by finding
subareolar glandular tissue >0.5 cm in diameter and is usually bilateral. Causes include:

• medications (spironolactone, cimetidine, antiandrogens, 5α-reductase inhibitors,

protease inhibitors)
• opioid use
• cirrhosis, CKD
• hypogonadism, hyperthyroidism
• germ cell tumors

Testing
In patients without an obvious cause, obtain hCG and 8 AM fasting testosterone and
estradiol levels.

Treatment
Treatment can be effective during the early proliferative phase. Testosterone is indicated
for confirmed hypogonadism; otherwise, choose selective estrogen receptor modulators
and aromatase inhibitors.

Don't Be Tricked
• Differentiate gynecomastia from pseudogynecomastia, which is fat deposition
typically seen in men with obesity.
• Obtain mammography for unilateral, nontender, or fixed masses to diagnose
breast cancer.

45
Hypercalcemia and
Hyperparathyroidism
Diagnosis
Primary hyperparathyroidism is the most common cause of hypercalcemia in
outpatients. Hypercalcemia is often discovered incidentally. Less common presentations
are kidney stones, osteoporosis, pancreatitis, and fractures (osteoporosis). Hypercalcemia
may also occur with the use of lithium (PTH mediated) or thiazide diuretics (non-PTH
mediated) and in the setting of excessive ingestion of vitamin D and calcium.

Malignancy is the most common cause of hypercalcemia in hospitalized patients.

Sarcoidosis may be associated with hypercalcemia (10% of patients) and hypercalciuria

(50% of patients).

Study Table: Causes of Hypercalcemia

Diagnosis Key features include hypercalcemia and…

Primary PTH elevated (80%) or inappropriately normal (20%);
hyperparathyroidism phosphorus low

X-rays may show chondrocalcinosis or osteitis fibrosa cystica

(rare)
Humoral PTH suppressed; phosphorus normal or low
hypercalcemia of
malignancy PTH-related protein may be elevated but is not needed for
diagnosis
Local osteolytic PTH suppressed; phosphorus normal or low
lesions
Lytic bone metastases result in increased mobilization of
calcium from the bone
Multiple myeloma PTH suppressed; phosphorus elevated

Look for patients presenting with new kidney injury and

anemia

Diagnose with serum and urine protein

immunoelectrophoresis
Granulomatous PTH suppressed; phosphorus elevated; calcitriol elevated
disease (sarcoidosis

46
Study Table: Causes of Hypercalcemia

Diagnosis Key features include hypercalcemia and…

and TB) and B-cell
lymphoma
Milk-alkali PTH suppressed; phosphorus, creatinine, carbon dioxide
syndrome elevated

Consider in healthy persons in whom primary

hyperparathyroidism has been excluded

Excessive ingestion of calcium carbonate to treat/prevent

osteoporosis
Hyperthyroidism Hypercalcemia is a frequent incidental finding in
hyperthyroidism caused by direct stimulation of osteoclasts
by thyroid hormone

Hypercalcemia requiring acute intervention is most often associated with a rapid rise in
serum calcium level and serum calcium >14 mg/dL. Symptoms may include change in
mental status and coma. It is most common in the setting of malignancy.

Testing
If hypercalcemia is confirmed, check PTH, phosphate, creatinine, and 25-hydroxyvitamin
D levels. If PTH is elevated or inappropriately normal in the setting of elevated serum
calcium, the most likely cause is primary hyperparathyroidism.

Don't Be Tricked
• In patients with hypercalcemia and normal PTH levels, measure urinary calcium
excretion to exclude familial hypocalciuric hypercalcemia.

If hyperparathyroidism is confirmed and surgery is indicated, imaging may be indicated

(ultrasound, sestamibi scan, CT, MRI).

Primary hyperparathyroidism is the most common manifestation of MEN1.

Treatment
For severe, symptomatic hypercalcemia, select:

• volume resuscitation with 0.9% saline

• IV bisphosphonates

47
 • oral glucocorticoid therapy (if caused by multiple myeloma, B-cell lymphoma, or
sarcoidosis)

Parathyroidectomy is indicated for patients with primary hyperparathyroidism and

hypercalcemic complications, such as kidney stones, bone disease, or previous episodes
of hypercalcemic crisis.

Asymptomatic patients are surgical candidates if they have any of the following:

• serum calcium level >1 mg/dL above the upper limit of normal
• creatinine clearance <60 mL/min
• T-score <−2.5 or vertebral fracture
• age <50 years

Watch for a precipitous fall in the serum calcium level caused by relative
hypoparathyroidism after parathyroidectomy (“hungry bone” syndrome). Monitor serum
calcium after surgery, and give oral calcium if mild hypocalcemia develops.

Treat patients who are not candidates for parathyroidectomy with cinacalcet or
bisphosphonates.

Don't Be Tricked
• Loop diuretics are not recommended in the treatment of hypercalcemia unless
kidney failure or HF is present, in which case, volume expansion should precede
the administration of loop diuretics to avoid hypotension and further kidney
injury.

Test Yourself
A 44-year-old man has a 1-year history of fatigue and poor concentration. His
serum calcium level is 10.9 mg/dL, serum phosphorus level is 2.8 mg/dL, and
PTH level is 75 pg/mL.

Answer: For diagnosis, choose primary hyperparathyroidism and measure serum

vitamin D levels. For management, select parathyroidectomy.

Multiple Endocrine Neoplasia

Diagnosis

48
Study Table: Multiple Endocrine Neoplasia Types 1 and 2

MEN1 MEN2
Multigland Multigland hyperparathyroidism is the least common
hyperparathyroidism is manifestation
the most common
manifestation
Pituitary neoplasms Medullary thyroid cancer is the most common
associated with manifestation and may be associated with a palpable
prolactinoma(amenorrhea, neck mass
erectile dysfunction),
acromegaly (enlargement
of hands, feet, tongue;
frontal bossing), Cushing
disease (bruising,
hypertension, central
obesity, hirsutism)
Pancreatic Pheochromocytoma (hypertension, palpitations)
NETs associated with
gastrinoma (diarrhea,
ulcers), insulinoma
(fasting hypoglycemia),
vasoactive intestinal
polypeptide-secreting
tumor (watery diarrhea,
hypokalemia), carcinoid
syndrome (diarrhea,
flushing, right heart
valvular lesion)

Don't Be Tricked
• About 50% of patients with primary hyperparathyroidism have coexisting vitamin
D deficiency, and serum and urine calcium levels may be decreased. Select
measurement of serum vitamin D levels in all patients with hyperparathyroidism.

Hypocalcemia
Diagnosis

49
Most cases of hypocalcemia are caused by low serum albumin levels; the ionized calcium
concentration is normal. Total calcium declines by 0.8 mg/dL for each 1 g/dL decrement
in serum albumin concentration.

Symptoms and Signs

Look for:

• circumoral and acral paresthesias

• carpopedal spasm
• positive Trousseau sign
• positive Chvostek sign

Causes

Autoimmune hypoparathyroidism (low PTH) occurs as an isolated defect or as part of

polyglandular autoimmune syndrome type 1 in association with mucocutaneous
candidiasis, adrenal insufficiency, hypogonadism, and malabsorption.
Hypoparathyroidism may also occur secondary to surgical excision or vascular injury to
the parathyroid glands.

In addition to hypoparathyroidism, hypocalcemia associated with elevated PTH may

result from:

• vitamin D deficiency
• hypomagnesemia
• severe pancreatitis
• rhabdomyolysis
• kidney injury
• tumor lysis syndrome

Order calcium, phosphate, magnesium, creatinine, PTH, 25-hydroxyvitamin D, albumin,

and/or ionized calcium tests. Order an ECG to evaluate for QT interval prolongation.

Study Table: Differential Diagnosis of Hypocalcemia

Diagnosis Key features include hypocalcemia and…

Hypoparathyroidism Hyperphosphatemia; low PTH and variable vitamin D levels
CKD Hyperphosphatemia; elevated PTH and low 1,25-
dihydroxyvitamin D levels
Vitamin D Hypophosphatemia; bone tenderness or fibromyalgia-like
deficiency syndrome, weakness, gait difficulty, osteomalacia

50
Study Table: Differential Diagnosis of Hypocalcemia

Diagnosis Key features include hypocalcemia and…

Impaired PTH Magnesium deficiency (small bowel bypass, diarrhea,
secretion and PTH alcoholism, diuretic therapy)
resistance
“Hungry bone” Recent parathyroidectomy
syndrome

Treatment
Treat acute symptomatic hypocalcemia with IV calcium gluconate and vitamin D.
Chronic hypocalcemia is treated with oral calcium supplements and vitamin D. Choose
the type of vitamin D based on the presence of underlying disease:

• kidney disease: calcitriol (1,25-dihydroxyvitamin D)

• liver disease: 25-hydroxycholecalciferol
• any other cause of hypocalcemia: cholecalciferol (D3) or ergocalciferol (D2)

The main adverse effect of therapy is hypercalciuria and nephrolithiasis. Correct

hypomagnesemia with magnesium supplements.

Test Yourself
A 46-year-old woman has cramps in her hands and feet. She has pernicious
anemia and Hashimoto thyroiditis. Her serum calcium level is 7.9 mg/dL, and her
serum phosphorus level is 4.1 mg/dL.

Answer: For diagnosis, choose autoimmune hypoparathyroidism and select a

serum PTH level.

Osteoporosis
Screening
The USPSTF recommends screening bone mineral density with DEXA in women ≥65
years and in postmenopausal women <65 years who are at increased risk as determined
by a formal clinical risk assessment tool (e.g., FRAX).

The American College of Rheumatology recommends that patients anticipating receiving

>3 months of glucocorticoid treatment should have bone mineral density testing within 6
months of starting glucocorticoid therapy, including:

51
 • all patients aged ≥40 years
• patients aged <40 years with osteoporosis risk factors or a fragility fracture

Screen men and women with risk factors for secondary osteoporosis (glucocorticoid use,
hyperparathyroidism, ADT [men], malabsorption).

Don't Be Tricked
• Do not repeat annual DEXA in women with normal DEXA results without risk
factors. The optimal screening interval is unknown.

Diagnosis
Osteoporosis is characterized by an increased predisposition to fractures.

• DEXA T-score of −1.0 to −2.4 defines osteopenia.

• DEXA T-score of ≤−2.5 defines osteoporosis.
• Osteoporosis is also diagnosed by a history of fragility fracture (fracture from a
fall at standing height or lower).

Causes

The most common cause of osteoporosis in women is estrogen deficiency and in men is
testosterone deficiency.

Secondary causes include:

• hyperthyroidism, hyperparathyroidism, Cushing syndrome

• malabsorption (Crohn disease, intestinal resection, celiac disease)
• rheumatoid arthritis
• medications (excessive thyroid hormone, glucocorticoids, phenobarbital,
phenytoin, thiazolidinediones)
• multiple myeloma
• CKD, chronic liver disease
• vitamin D deficiency

Testing
In the absence of bone fracture, primary osteoporosis is associated with normal
laboratory testing.

Reasonable tests for the evaluation of secondary osteoporosis

include CBC; TSH; calcium, phosphorus, and eGFR; liver chemistry tests; ESR; serum

52
25-hydroxyvitamin D level (if vitamin D deficiency is suspected); and tTG antibodies (if
celiac disease is suspected).

Treatment
Encourage all patients to:

• stop smoking
• reduce alcohol intake
• begin resistance exercises
• supplement calcium and vitamin D intake

Indications for antiresorptive therapy:

• osteoporosis
• osteopenia (if additional high-risk factors are present)
• previous fragility fracture
• vertebral or hip fracture

The FRAX estimates the 10-year probability of hip fracture and major osteoporotic
fracture. Antiresorptive treatment is cost effective when the risk of major osteoporotic
fracture is ≥20% or the risk of hip fracture is ≥3%.

Treatment options:

• alendronate or risedronate is first-line therapy

• denosumab (monoclonal antibody that inhibits osteoclast activation) may be
preferred in patients with stage 4 CKD and in those intolerant of or incompletely
responding to bisphosphonates

Oral bisphosphonates are contraindicated in patients with CKD or esophageal disease. IV

zoledronate (once yearly) is an alternative therapeutic option.

Don't Be Tricked
• The effects of denosumab are not sustained when treatment is stopped, and bone
loss is accelerated.

No recommended duration of therapy is specified. Stopping therapy after 3 years (IV

therapy) or 5 years (oral therapy) is reasonable in women who have a stable BMI, have
no history of fracture, and are at low risk for fracture. Recommended duration of the drug
holiday is unknown.

Drugs for osteoporosis have various adverse effects:

53
 • Oral bisphosphonate therapy may lead to erosive esophagitis and atypical hip
fracture.
• IV bisphosphonate therapy and denosumab can lead to osteonecrosis of the jaw.

Don't Be Tricked
• Do not use estrogen replacement therapy for osteoporosis in postmenopausal
women.
• IV bisphosphonates are contraindicated in patients with severe hypocalcemia and
CKD.

Follow-up
Although no consensus exists, follow-up DEXA 24 months after beginning therapy for
osteoporosis is reasonable.

Test Yourself
An 82-year-old woman has been taking thyroid hormone since age 31 years. She
has lost about 7.6 cm (3.0 in) in height. Serum TSH level is <0.01 μU/mL (normal
0.5 to 5.0 μU/mL).

Answer: For diagnosis, choose thyroid hormone–induced osteoporosis. For

management, reduce the thyroid hormone dose and schedule DEXA.

Osteomalacia
Diagnosis
Osteomalacia results from failure of the organic matrix of bone to mineralize because of
lack of available calcium or phosphorus. Most cases of osteomalacia are related to
abnormalities in vitamin D.

Symptoms and signs include:

• fatigability, malaise, and bone pain

• proximal muscle weakness
• looser zones (bands perpendicular to the bone surface visible on x-rays)
• hypocalcemia and hypophosphatemia
• elevated serum alkaline phosphatase level

Testing
54
Evaluate for underlying conditions that may lead to intestinal malabsorption of vitamin
D, such as celiac disease, or abnormalities in vitamin D metabolism, such as liver and
kidney disease. Diagnosis is confirmed with bone biopsy when necessary.

Treatment
If osteomalacia is secondary to vitamin D deficiency, treat with oral ergocalciferol 1000
to 2000 U/d and elemental calcium 1 g/d.

Don't Be Tricked
• Not all fractures in older adult patients are caused by osteoporosis. Look for
osteomalacia, particularly in nursing-home residents.

• Vitamin D Deficiency
• Screening
• The USPSTF concludes that evidence is insufficient to assess the balance
of benefits and harms of screening for vitamin D deficiency in
asymptomatic adults.
• Diagnosis
• Prolonged and severe vitamin D deficiency will cause secondary
hyperparathyroidism; osteomalacia in adults; and symptoms of bone pain,
muscle weakness (including difficulty walking), and fracture.
• Testing
• In assessing serum levels of vitamin D, concentrations of 25-
hydroxyvitamin D are the best indicator of vitamin D status.
• The Institute of Medicine has determined that a vitamin D level of ≥20
ng/mL is sufficient.
• Treatment
• The USPSTF concludes that evidence is insufficient to recommend vitamin
D and calcium supplementation, alone or combined, for the prevention of
fractures in men and premenopausal women.
• Treatment options for prevention and treatment of vitamin D deficiency
vary by indication and underlying disease.

Paget Disease
Diagnosis

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Paget disease is a focal disorder of bone remodeling that leads to greatly accelerated rates
of bone turnover, disruption of the normal architecture of bone, and sometimes gross
deformities of bone (enlargement of the skull, bowing of the femur or tibia). Most
patients are asymptomatic, and the disease is suspected when an isolated elevation of
alkaline phosphatase is detected in the absence of liver disease.

Symptoms and signs include:

• bone pain, fractures

• cranial nerve compression syndromes, spinal stenosis, nerve root syndromes
• high-output cardiac failure

Testing
If the serum alkaline phosphatase (bone) level is elevated in an asymptomatic patient,
order a bone scan and follow-up x-rays of areas that localize radionuclide. In
symptomatic patients, obtain x-rays of the painful area. X-rays will reveal these
pathognomonic pagetic lesions:

• focal osteolysis with coarsening of the trabecular pattern

• “cotton wool” skull
• cortical thickening

Figure 8. Paget Disease:

X-ray showing “cotton wool” appearance of the skull typical of Paget
disease.

56
Treatment
Indications to treat Paget disease include bone pain, radiculopathy, or involvement of a
weight-bearing bone or joint regardless of symptoms. Treatment is typically a one-time
dose of IV zoledronic acid.

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