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III. EVALUATION
A. History.
History is quite important and should include standard items, such as onset,
duration, aggravating factors, relieving factors, and associated symptoms. Additionally, other
factors should be considered, such as the following:
1. Exposure History. Are any other family members or close contacts ill? Is there a history
of exposure to standing water, mosquitoes, or foreign travel?
2. Are there underlying illnesses or is there a significant chance of immunologic compro-
mise, such as undiagnosed HIV infection?
B. Physical Examination
1. The lesions in the distribution should be carefully examined. The rash should be clas-
sified as petechial, maculopapular, vesiculobullous, erythematous, or urticarial. The dis-
tribution of the rash should be noted. For instance, rubella and rubeola generally begin
on the face and spread to the trunk, whereas the petechiae of Rocky mountain spotted
fever tend to occur on the ankles and wrists first.
2. A general physical examination should be conducted. Areas of particular concern are
as follows:
a. Head, eyes, ears, nose, and throat examination. Koplik spots are pathognomonic
for rubeola. The discovery of a tick tends to support the diagnosis of Rocky mountain
spotted fever. Sinusitis may present as a source for meningococcemia. Pharyngitis in
the young adult with diffuse erythema may be due to C. haemolyticum. The presence
of mucous membrane swelling may indicate early anaphylaxis.
b. Lung examination. Wheezing on examination, especially in a patient who has
recently received medications or contrast dye, can indicate anaphylaxis. Evidence of
pneumonia is consistent with psittacosis and Mycoplasma.
c. Cardiac examination. Cardiovascular collapse is associated with meningococcemia
another sepsis. A new murmur may indicate subacute bacterial endocarditis in the
patient with subungual or scleral petechiae.
d. Genital examination. Purulent urethral drainage or evidence of pelvic inflamma-
tory disease supports the consideration of gonorrhea. A chancre supports a diagnosis
of syphilis, although palmar lesions often occur well after the healing of the initial
chancre.
e. Joint examination and extremities. A petechial rash near the ankles and wrists is sug-
gestive of Rocky Mountain spotted fever. Evidence of joint swelling supports diagnosis
of meningococcemia or gonococcemia. A maculopapular rash may be seen in juvenile
rheumatoid arthritis and other rheumatologic conditions as well.
f. Neurologic examination. Evidence of meningitis supports a diagnosis of meningo-
coccemia. Patients with Rocky Mountain spotted fever may also have meningeal signs.
C. Testing. Testing should be directed by the suspected illnesses, with life-threatening ill-
nesses being tested for upon reasonable suspicion. A complete blood count is generally
useful, although life-threatening sepsis often presents without significant elevation of the
white blood cell count. In general, a blood culture should be obtained in all patients with
petechial rashes and in those with signs of cardiovascular collapse.
IV. DIAGNOSIS. On the basis of the history and physical examination, the likelihood of various
illnesses can be assessed. Patients who appear toxic should be treated as septic until initial labo-
ratory tests and culture results can be evaluated (4).
REFERENCES
1. Schlossberg D. Fever and rash. Infect Dis Clin North Am 1996;10(1):101–110.
2. Drolet BA, Baselga E, Esterly NB. Painful, purpuric plaques in a child with fever. Arch Dermatol
1997;133(12):1500–1501.
3. American Journal of Medicine. Fever, nausea, and rash in a 37-year-old man [clinical conference]. Am
J Med 1998;104(6):596–601.
4. Dellinger RP. Current therapy for sepsis. Infect Dis Clin North Am 1999;13(2):495–509.
308
13.7
I. BACKGROUND. Urticaria is composed of wheals, which are transient erythematous, edema-
tous, pruritic papules and plaques. They are usually surrounded by a red or white halo caused
by the release of histamine and other vasoactive substances from mast cells. Lesions usually are
itchy and last less than 24 hours.
II. PATHOPHYSIOLOGY
A. Etiology.
Urticaria is classified as immunologic, nonimmunologic, or idiopathic.
Immunologic Type I or Type III immunoglobulin (Ig)E-mediated reactions are the main
causes of acute urticaria. Circulating antigens such as foods (milk, eggs, wheat, shellfish,
nuts) and drugs (penicillins, cephalosporins) interact with membrane-bound IgE to release
histamine which cause localized vasodilation. Nonimmunologic causes such as aspirin or
nonsteroidal anti-inflammatory drugs can cause direct release of histamine (1).
B. Epidemiology. Urticaria is a common condition; 1–5% of the population may suffer
from this condition during their lifetime. It is more common in women (2).
Urticaria is defined as “acute” (new onset or recurrent episodes, of less than 6 weeks
duration) or “chronic” (recurring episodes of more than 6 weeks duration).
III. EVALUATION
A. History.
History is an important part of diagnosis, because the lesions are often not pres-
ent at the clinic visit. When assessing a patient presenting with possible urticaria, a helpful
approach to the problem is as follows:
1. Ask the patient if he or she knows what triggers the hives. Often the patient has already
determined the cause or has narrowed down the list of possibilities.
2. Take a detailed history for specific foods, any known food additives, medications, recent
respiratory infections, bites, contact, inhalants, or a history of systemic disease, particu-
larly autoimmune diseases or neoplasms.
3. Ask about the timeline of the disease. When does it occur? How long does it last? Is it
related to cold, exertion, heat, or physical trauma or sun exposure?
4. Ask if there is any related swelling of soft tissue, such as the eyelids and lips.
5. Ask about history of personal/family history of atopy or a family history of autoimmune
disease.
B. Physical Examination. Look for well-defined, erythematous, edematous papules or
plaques, often with a pale center. Individual lesions last less than 24 hours. In contrast, in
urticarial vasculitis, individual lesions are fixed and persist beyond 24 hours. Lesions may
differ in size from 2–5 mm to over 30 cm and may be annular, serpiginous, or irregularly
shaped. Edema of the mucous membranes may be present.
Angioedema, which manifests with swelling of the face, bowel, or part of an extremity,
is seen in approximately 50% of urticaria cases and can last for several days.
C. Testing
1. Laboratory testing is not routinely indicated for acute urticaria.
2. In chronic urticaria, perform a complete blood count with differential, sedimentation
rate, liver function testing, a urinalysis, and consider thyroid function tests.
3. If individual lesions persist for more than 24 hours, it may be helpful to biopsy a lesion to
rule out urticarial vasculitis. If a vasculitis is present, additional testing should include C3,
C4, CH50 levels, hepatitis B and C serologies, antinuclear antibody (ANA), cryoglobulins,
immunoglobulin levels, serum protein electrophoresis and urine protein electrophoresis.
4. Provocative tests (such as the ice cube test or strenuous exercise) may help establish a
diagnosis of cold or physical urticaria. However, the provider should be cognizant of the
risk of precipitating anaphylaxis.
Urticaria
Omar Shamsaldeen
309
5. Imaging studies such as sinus, dental films and chest X-ray may help to rule out infection
or neoplasms.
6. Skin testing or radioallergosorbent assays are ordered if hypersensitivity to a particular
allergen is suspected.
IV. DIAGNOSIS
A. Differential Diagnosis.
The diagnosis of urticaria is made clinically. Other skin problems
that present with urticarial lesions include urticarial vasculitis (painful, purpuric, and last
>24 hours), drug eruptions, viral exanthema, bullous pemphigoid in elderly patients, ery-
thema multiforme (acral, and lasting >24 hours) and angioedema.
B. Clinical Manifestations. Although the lesions of urticaria are distinctive, the various
underlying conditions that trigger the skin’s response are numerous and varied in their clini-
cal manifestations. Virtually all patients with urticaria complain of pruritus in addition to
the rash.
REFERENCES
1. Habif TP, Urticaria and angioedema. In: Clinical dermatology, 5th ed. Mosby, Elsevier, 2009:181–193.
2. Grattan, C., & Kobza-Black, A. (2007). Urticaria and angioedema. In J. Bolognia, J. Jorizzo, &
R. Rappini, Dermatology (2nd ed., pp. 261–276). St. Louis: Elsevier-Mosby.
13.8
I. BACKGROUND. A vesicle is a liquid-filled cavity that is less than 1 cm in diameter. A bulla is
a similar lesion larger than 1 cm in diameter. Vesiculobullous eruptions (VBE) are commonly
termed blistering diseases.
II. PATHOPHYSIOLOGY
A. Etiology.
There are many causes of VBE. These include infectious conditions such as her-
pes simplex (HS) infection, inflammatory causes like dyshidrotic eczema (DE) and contact
dermatitis, autoimmune causes such as bullous pemphigoid (BP), and hereditary causes like
epidermolysis bullosa (EB). Systemic conditions, such as allergic vasculitis, and porphyria
cutanea tarda (PCT) often present with VBE. Drug-induced conditions, such as Stevens-
Johnson syndrome/toxic epidermolysis necrolysis (SJS/TEN) are also seen. Environmental
factors can contribute to the development of VBE. For example, sun exposure, alcohol
ingestion, as well as certain medications and infections are thought to contribute to the
induction of PCT (1). Sun exposure, stress, menses, smoking, and alcohol ingestion can
induce recurrent HS infection.
B. Epidemiology
1. The patient age group can provide the physician with clues to the diagnosis:
a. Newborns. Most commonly present with hereditary or infectious conditions.
Examples include EB, pemphigus neonatorum, and syphilitic pemphigus.
b. Children. The most common causes in this age group are infections. These include
varicella, primary HS, hand, foot, and mouth (HFM) disease, and bullous impetigo (BI).
c. Adults. Infectious causes continue to predominate, but inflammatory and autoim-
mune causes become increasingly common. These include PCT, pemphigus vulgaris
(PV), DE, and dermatitis herpetiformis (DH). A variant of BP, pemphigoid gestatio-
nis may occur during pregnancy or the puerperium.
Vesicular and Bullous
Eruptions
Ahmed Salem Al Dhaheri and Hassan Galadari
310
In addition, rarer causes, such as linear immunoglobulin A disease (linear IgA
bullous dermatosis) may be seen.
d. Elderly. Autoimmune diseases become commoner in this age group. For example, the
median age of presentation of BP is 80 years.
2. Examples of conditions that occur commonly in all age groups include allergic contact
dermatitis, allergic vasculitis, SJS/TEN, insect bites, and partial thickness (second-
degree) burns.
III. EVALUATION
A. History
1. Pain or Pruritus. Most of the VBE are asymptomatic; however, some are associated
with discomfort. For example, contact dermatitis and DH are commonly associated with
pruritus (1). Herpes zoster (HZ) can cause pain and/or a burning sensation preceding the
skin eruption.
2. Family History. A positive family history of a blistering disease in a newborn may
suggest a particular diagnosis. A history of similar eruptions among other siblings or
classmates implicates an infectious etiology of VBE.
3. Onset and Duration. VBE can be acute or chronic. Causes of VBE that are more likely
to present acutely include SJS/TEN, varicella, BI, HZ, allergic vasculitis, HFM disease,
and PV. Conditions that are more likely to present indolently include DH, DE, BP, EB,
and PCT. Some causes can be episodic and recurrent, such as acute contact dermatitis
and HS infection.
B. Physical Examination
1. Appearance. In patients who appear systemically ill, or toxic, consider SJS/TEN, PV, or
primary HS infection as possible etiologies.
2. Presence of Fever. Patients with infectious etiologies, particularly those with varicella,
HFM, primary HS or BI may have a fever, as may patients with SJS/TEN.
3. Presence of Oral Lesions. The presence of oral lesions should be sought in every
patient, since some serious VBEs can involve the oral cavity, such as STS/TEN. It also
can guide the provider to the diagnosis of PV, varicella, or HFM. The skin lesions of PV
may appear months after the onset of oral lesions (2).
4. Vesicles versus Bullae. Vesicles and bullae are the primary lesions in VBEs. Clinically,
the size of the lesions may overlap, and it may be difficult to distinguish whether the
lesions are vesicular or bullous. This is particularly true when, as frequently happens,
the lesions rupture, and the patient will present with secondary lesions such as erosions,
ulcers, and/or crusts.
Conditions such as HS infection, varicella, HZ, contact dermatitis, DE, hemorrhagic
vasculitis, HFM disease, Kaposi’s varicelliform eruption (KVE or eczema herpeticum),
and DH tend to present with vesicles. PV, BP, BI, PCT, SJS/TEN, TEN, and EB tend
to present with bullae. The presence of larger bullae or erosions tends to occur more
commonly in bullous diseases.
5. Lesion Characteristics and Distribution. Blisters of BI rupture easily and often form a
honey-colored crust. BI most frequently affects the face, particularly around the mouth
and nose, or at sites of trauma. In PV, intact flaccid blisters are occasionally found.
Involvement of the scalp, face, upper torso, and oral mucosa is common. In BP, blisters
are tense and large, urticarial patches and plaques often precede the blister formation.
The trunk, extremities, and flexures are commonly involved. Linear IgA disease presents
with small vesicles and/or large bullae in the groin, buttocks, trunk, and extremities,
with occasional oral involvement. In PCT, the patient usually presents with erosions and
blisters on sun-exposed areas, such as the dorsum of the hands. Often these form painful
sores that heal slowly, resulting in depigmentation and scarring (1). Contact dermatitis
occurs at sites of contact with allergenic materials, and DE tends to involve the lateral
sides of the fingers and the palms. HFM syndrome presents with lesions on the hands,
feet, in the mouth, and on the buttocks. HZ is generally confined to one or two adjacent
dermatomes and is unilateral. KVE will occur in areas of existing dermatitis.
311
C. Testing
1. Tzanck Smear. This test is done by unroofing an intact blister and scraping its base. The
material is smeared on a slide, stained, and examined under microscopy for the presence
of multinucleated giant cells (3).
2. Biopsy. When the clinical diagnosis is uncertain, a skin biopsy is helpful. When biopsy-
ing vesicles, a biopsy of the entire vesicle with adjacent normal skin when possible is
ideal. With bullae, the edge of the lesion should be biopsied, with the roof of the bulla
included, as well as some adjacent normal skin (1). Direct immunofluorescence micros-
copy, and other techniques are helpful in distinguishing between various VBEs in the
clinical setting.
IV. DIAGNOSIS
A. Differential Diagnosis.
An accurate differential diagnosis and subsequent diagnosis is
greatly facilitated by obtaining a thorough history and physical examination. If the diagnosis
remains unclear, particularly if a potentially serious condition may exist, biopsy or referral
may be helpful to confirm a diagnosis.
REFERENCES
1. Welsh B. Blistering skin conditions. Aust Fam Physician 2009;38(7):484–490.
2. Bickle KM, Roark TR, Hsu SH. Autoimmune bullous dermatoses: a review. Am Fam Physician
2002;65(9):1861–1870.
3. Brodell RT, Helms SE, Devine M. Office dermatologic testing: the Tzanck preparation. Am Fam
Physician 1991;44(3):857–860.
312
CHAPTER 14
Endocrine and
Metabolic Problems
Arwa Abdulhaq Nasir
14.1
I. BACKGROUND. Diabetes mellitus (DM) refers to a group of metabolic disorders characterized
by hyperglycemia resulting from deficient insulin secretion and/or insulin action. The clinical
classes of DM are type 1, type 2, gestational, and other specific types secondary to a variety of
causes. The classification of DM is based on the etiology of the disorders as currently under-
stood (1). Inadequate glucose control leads to both micro- and macrovascular complications
(2). The Centers for Disease Control and Prevention lists diabetes as the seventh leading cause
of death in the United States (3).
II. PATHOPHYSIOLOGY
A. Etiology
1. Type 1. Type 1 diabetes is further categorized as type 1A or type 1B diabetes. Both
result from autoimmune or idiopathic destruction of pancreatic beta cells and result
in absolute insulin deficiency. Type 1A is associated with human leukocyte antigen
(HLA)-related genes DQA and DQB and is suggested by the presence of numerous
autoantibodies. These include anti-glutamic acid decarboxylase (GAD), anti-islet cell
autoantigen 512, and anti-insulin antibodies. Type 1B is idiopathic, lacking any identifi-
able autoimmune markers or HLA association.
2. Type 2. Type 2 becomes manifest after several years of progressive insulin resistance within
muscle, fat, and liver cells. To maintain fasting euglycemia, endogenous insulin secretion
is often increased early in the prediabetic phase. Over time, insulin production can subse-
quently decline, postprandial glucagon becomes increasingly nonsuppressible, and patients
may require a transition to insulin therapy. Glucagon-like peptide 1 (GLP-1) is secreted
by intestinal L cells during digestion, and it influences gastric emptying, promotes insulin
secretion, and decreases glucagon secretion. It, too, behaves aberrantly in type 2 DM.
B. Epidemiology
Currently, 25.8 million adults and children in the United States are estimated to have dia-
betes, with the number of cases increasing at a rate of 1.5 million per year (3). One-third of
the people born in the United States in 2000 are projected to develop diabetes during their
lifetime. As measured by fasting glucose values or hemoglobin A1C levels studied between
2005 and 2008, 35% of US adults aged 20 years or older were prediabetics. Among those 65
years or older, up to 50% are prediabetic. Collectively, this means that roughly 79,000,000
American adults aged 20 or older are at significant risk for diabetes (3).
A. Type 1. Type 1 diabetes accounts for approximately 5% of all diagnosed cases in adults.
About 215,000 US residents under 20 years of age have diabetes and the vast majority are
Diabetes Mellitus
Michael J. Hovan and Curtiss B. Cook
313
classified as having type 1 diabetes (3). Despite the increasing rate of type 2 diabetes among
children, type 1 diabetes still accounts for approximately two-thirds of new cases of diabetes
in patients under 20 years of age (4). In the United States, Caucasians face the highest risk for
type 1 diabetes among ethnic and racial groups, with an incidence of 23.6 per 100,000 (5).
In contrast, type 1B diabetes occurs more often in individuals of Asian or African descent.
B. Type 2. Type 2 DM accounts for 95% of cases of diabetes overall and remains rare in
individuals under age 20 years, although the rising rates of obesity among US youths have
led to a corresponding increase in the rates of type 2 DM among younger patients in the last
decade. Among Caucasians aged 10–19 years, the rate of new cases remains higher for type 1
than for type 2 diabetes. For blacks and Hispanics aged 10–19 years, the rates of new cases
are equally split between types 1 and 2. In Asian, Pacific Islander, and Native Americans
aged 10–19 years, the rates of new cases of type 2 exceed those of type 1. Type 2 remains
rare under age 10 years in all groups.
C. Gestational DM. Approximately 2–10% of pregnancies are complicated by gestational
diabetes. In the 20 years subsequent to the pregnancy, 35–60% will develop diabetes (3).
III. EVALUATION
Although type 1 and type 2 diabetes can present with similar symptoms of polyuria and poly-
dipsia, the onset of type 1 typically occurs more precipitously. Accurate screening and diagnosis
is important in order to identify those at risk and to reduce diabetic complications.
A. Physical Examination
The physical findings and diabetes are influenced by the duration and severity of the disease.
With acute hyperglycemia, tachycardia, poor skin turgor, dry mucous membranes, and
orthostasis result from glucose-induced osmotic diuresis. Ketonemia may be identified by
a fruity odor of respiratory expiration and an altered mental status if severe. With longer,
more established disease, diminished lower extremity sensory function measured by mono-
filament testing and altered vibratory sensation detected with a 128 Hz tuning fork suggests
neuropathy. Hypertension and edema suggest possible nephropathy. Visual impairment is
a late finding in individuals with diabetic retinopathy, and the physical exam may show
nerve fiber infarcts, cotton wool spots, intraretinal hemorrhages, hard exudates, and dilated
or tortuous vessels.
B. Testing
The 2011 American Diabetes Association (ADA) guidelines define diabetes with any one
of the following parameters, as long as confirmed with repeat testing (unless unequivocal
hyperglycemia): hemoglobin A1C > 6.5%, fasting glucose >126 mg/dL, a 2-hour plasma
glucose ≥200 mg/dL following a 75 g anhydrous glucose challenge, or classic symptoms
and a random glucose ≥200 mg/dL (6). Prediabetes is defined as fasting glucose values
between 100 and 125 mg/dL, a 2-hour oral glucose tolerance test value of 140–199 mg/dL,
or a hemoglobin A1C of 5.7–6.4%. The hemoglobin A1C is the least sensitive diagnostic
test, while the oral glucose tolerance test remains the most sensitive. In the setting of discor-
dant values, the most abnormal test takes precedent over other values. Hemoglobin A1C is
excluded from diagnostic criteria in pregnancy.
For gestational diabetes, the ADA and the American College of Obstetrics and
Gynecology (ACOG) differ in their diagnostic approaches. The ADA suggests that a uni-
versal 75 g oral glucose tolerance test be performed between weeks 24 and 28 of gestation.
A fasting value ≥92 mg/dL, a 1-hour value ≥180 mg/dL, or a 2-hour value ≥153 mg/dL
confirms gestational DM. ACOG proposes a two-step process and states that very low-risk
individuals do not require testing. A 1-hour 50 mm oral glucose tolerance test is first given,
and if the plasma glucose is >140 mg/dL, then a confirmatory test is performed. This
consists of a 3-hour 100 g oral glucose tolerance test. Diagnostic cutoffs include a fasting
value >95 mg/dL, a 1-hour value ≥180 mg/dL, a 2-hour value ≥155mg/dL, or a 3-hour
value ≥140 mg/dL. All women with gestational DM should be retested in 6–12 weeks
postpartum and every 3 years thereafter because of their lifelong increased risk of diabetes.
C. Genetics
Type 1A DM has HLA associations with linkages to the DQA and DQB genes, while type
1B is idiopathic. Type 2 diabetes is influenced by both modifiable and non-modifiable risk.
314
Taylor’s DifferenTial Diagnosis Manual
Non-modifiable risks include family history, ethnicity, and advanced age. Modifiable and
nongenetic factors include sedentary lifestyle, high body mass index, and central adiposity (7).
IV. DIAGNOSIS
A. Clinical manifestations.
Determination of the specific type of diabetes is essential
to providing appropriate treatment. Prior to the development of acute hyperglycemia
(manifested as polyuria, polyphagia, and usually ketosis), most type 1 patients appear
healthy prior to the diagnosis.
1. Type 1. Nonobese children, adolescents, and young adults account for most cases
of type 1 diabetes. Since beta-cell destruction most often occurs rapidly over the
course of days or weeks, diabetic ketoacidosis (DKA), abrupt weight loss, polyuria,
polydipsia, and lethargy usually herald the diagnosis. The most serious presentation,
DKA, is more likely to occur in children (8). DKA is defined as a glucose exceed-
ing 200 mg/dL and metabolic acidosis is designated by a pH <7.3 or bicarbonate
<15 mEq/L. Additional common features include fatigue, dehydration, nausea,
anorexia, hyperventilation (Kussmaul respiration), and acute visual and mental
status changes. Asymptomatic hyperglycemia as a silent presentation is rare in type
1 diabetes, due to the rapid destruction of beta cells and because polyuria usually
ensues once the serum glucose exceeds 180 mg/dL.
2. Type 2. Individuals with acanthosis nigricans, obstructive sleep apnea, hypertension,
vascular disease, positive family history, hyperuricemia, polycystic ovarian disease,
and nonalcoholic steatohepatitis face a greater risk of type 2 diabetes. At the time
of diagnosis, many individuals already have evidence of neuropathy, nephropathy,
or retinopathy. The typical type 2 diabetic patient is overweight or obese and older
than 40 years. Patients usually present with characteristic features of hyperglycemia,
including polyuria, polydipsia, and nocturia. Less specific and subtle clues to the
diagnosis might include poor wound healing, recurrent infections, and/or candidal
vulvovaginitis. An urgent presentation of type 2 diabetes involves a hyperosmolar
hyperglycemic state with marked glucose elevation, profound dehydration, but little
or no ketonemia. On rare occasions, DKA can occur in type 2 DM and is more likely
to occur in African American children (9).
3. Gestational DM. Pregnancy can precipitate an acute state of insulin resistance. Since
its pathogenesis is similar to type 2 DM, the clinical features are similar, though poly-
uria is sometimes mistakenly attributed to the gravid uterus’s effects on the bladder
rather than hyperglycemia. Delivery of an infant weighing >4.1 kg (9 lb) poses a future
risk of diabetes.
B. Differential diagnosis. Autoimmune antibody markers and a C-peptide assay help
distinguish type 1 from type 2 diabetes. C-peptide confirms whether endogenous insulin
production exists. Since proinsulin consists of insulin peptide and C-peptide, C-peptide
is removed from the proinsulin peptide when active insulin is generated. The absence of
C-peptide suggests total beta-cell failure. Its presence supports the production of endog-
enous insulin. Caution in the interpretation of C-peptide results is necessary since some
patients with type 1 diabetes, at least early in the course of autoimmune beta-cell destruc-
tion, may still produce some insulin secretion and therefore have measurable levels of
C-peptide. The presence of hyperglycemia and autoantibodies suggests type 1 disease, but
is not necessary for the diagnosis. These markers include islet cell autoantibodies, insulin
autoantibodies, autoantibodies targeting the 65 kDA isoform of GAD, and autoantibodies
targeting the phosphate-related 1A-2 molecule (10).
Clinical entities other than DM that present with polyuria include central and
nephrogenic diabetes insipidus, various hypothalamic disorders, psychiatric polydipsia,
postobstructive diuresis, and the effects of certain medications such as lithium. Transient
hyperglycemia can occur with acute severe illness, especially with the use of corticosteroids
and vasopressor/catecholamine agents, such as in the ICU setting. A new diagnosis of dia-
betes in this setting is cautioned, and new hyperglycemia detected in a hospitalized patient,
particularly if mild, should be reevaluated in an outpatient setting.
Chapter 14 • Endocrine and Metabolic Problems
315
14.2
I. BACKGROUND. The male breast consists of minimal amounts of adipose and glandular tis-
sues. An altered estrogen-to-testosterone ratio in a male may lead to gynecomastia, or prolifera-
tion of the glandular breast tissue (1).
II. PATHOPHYSIOLOGY. Gynecomastia is caused by a relative increase of estrogen in relationship
to androgens.
A. Physiologic gynecomastia has three peaks of age distribution: the newborn period,
adolescence, and men older than 50 years.
1. Newborn gynecomastia, which occurs in up to 90% of newborn boys, is due to the
transplacental transfer of maternal estrogens. This type of gynecomastia typically resolves
spontaneously within the first four weeks of life (2).
2. Pubertal gynecomastia occurs in about 50% of boys, presenting in the early teens and
corresponding to Tanner stage 3 or 4. This is due to an increase in estradiol concentra-
tion, delayed testosterone production, and increased sensitivity to estrogen at the tissue
level (2).
3. One-third to two-thirds of older adult males develop physiologic gynecomastia as a result
of age-related decreasing levels of circulating free testosterone (1).
Gynecomastia
Michelle L. Benes
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3. U.S. Department of Health and Human Services CfDCaP. National diabetes fact sheet: National
estimates and general information on diabetes and prediabetes in the United States, 2011, Atlanta, GA:
U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. 2011.
4. Liese AD, D’Agostino RB, Jr., Hamman RF, et al. The burden of diabetes mellitus among US
youth: prevalence estimates from the SEARCH for Diabetes in Youth Study. Pediatrics 2006
Oct;118(4):1510–1518.
5. Bell RA, Mayer-Davis EJ, Beyer JW, et al. Diabetes in non-Hispanic white youth: prevalence, inci-
dence, and clinical characteristics: the SEARCH for Diabetes in Youth Study. Diabetes Care 2009
Mar;32(Suppl 2):S102–S111.
6. American Diabetes Association. Standards of medical care in diabetes-2011. Diabetes Care 2011
Jan;34(Suppl 1):S11–S61.
7. Nyenwe EA, Jerkins TW, Umpierrez GE, Kitabchi AE. Management of type 2 diabetes: evolving
strategies for the treatment of patients with type 2 diabetes. Metabolism 2011 Jan;60(1):1–23.
8. Mallare JT, Cordice CC, Ryan BA, Carey DE, Kreitzer PM, Frank GR. Identifying risk factors for
the development of diabetic ketoacidosis in new onset type 1 diabetes mellitus. Clin Pediatr (Phila)
2003 Sep;42(7):591–597.
9. Sapru A, Gitelman SE, Bhatia S, Dubin RF, Newman TB, Flori H. Prevalence and characteristics
of type 2 diabetes mellitus in 9-18 year-old children with diabetic ketoacidosis. J Pediatr Endocrinol
Metab 2005 Sep;18(9):865–872.
10. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists
Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan.
Endocr Pract 2011 Mar-Apr;17(Suppl 2):1–53.
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B. Nonphysiologic gynecomastia can occur at any age due to medication use, substance
abuse, and several medical conditions.
1. Persistent pubertal gynecomastia is diagnosed when present in an adolescent male for
more than 2 years or past the age of 17 years and is not associated with other causes.
2. Medication and substance use are the most common causes of nonphysiologic gyne-
comastia. Long-term use of cimetidine, antipsychotics, antiretrovirals, prostate cancer
therapies, and spironolactone are commonly identified as transient causes, typically
resolving within 3 months of drug discontinuation. Anabolic steroid use, marijuana,
heroin, and amphetamines may lead to persistent gynecomastia (3).
3. Medical conditions such as cirrhosis, primary hypogonadism, malignant tumors, hyper-
thyroidism, and malnutrition may cause about 25% of nonphysiologic cases of gyneco-
mastia (4, 5). Over 50% of patients on hemodialysis for chronic renal failure will develop
gynecomastia.
4. Obesity is commonly associated with pseudogynecomastia, or proliferation of the adi-
pose component of the breast. Obesity may also lead to increased circulating estrogens
leading to true gynecomastia (2).
5. Approximately 25% of cases of gynecomastia are idiopathic (2).
III. EVALUATION
A. History.
A thorough history should be obtained. Other specific identifiable causes such
as medications, supplements, or illicit drug use should be sought. Systemic symptoms such
as weight loss should direct concern to the possibility of a malignancy, endocrinopathy, or
other underlying disease processes (1, 2).
B. Physical examination. A palpable, firm, glandular tissue mass under the nipple areolar
complex is consistent with gynecomastia. Increased deposition of adipose tissue is consistent
with pseudogynecomastia. Hard, irregular, or immobile masses, masses with associated skin
changes, nipple retraction, nipple discharge or adenopathy should alert the clinician to the
possibility of malignancy. Physical exam should also include a search for testicular changes,
liver disease, and thyroid abnormalities, indicating the presence of underlying disease
process as the cause of the gynecomastia (1, 2).
C. Laboratory testing. If findings from the history and physical exam suggest nonphysi-
ologic causes, targeted testing of liver, kidney, and thyroid function should be performed.
Serum β-hCG, dehydroepiandrosterone sulfate, and urinary 17-ketosteroid may be
obtained to help identify testicular or adrenal tumors. Elevated prolactin levels are associ-
ated with pituitary adenoma. Low luteinizing hormone and testosterone levels characterize
secondary hypogonadism. High luteinizing hormone levels in conjunction with low levels
of testosterone indicate primary hypogonadism (1).
D. Imaging and cytologic studies. Breast imaging, including mammography and ultra-
sound, is indicated when breast cancer is suspected. Fine needle aspiration for cytologic
sampling should be included in the evaluation if the concern for malignancy is not resolved.
IV. CLINICAL MANIFESTATIONS. Gynecomastia is bilateral in more than 50% of affected men, but
it may be unilateral or symmetric. It presents as a firm, mobile, or rubbery mass that may be slightly
tender and forms a symmetrical mount around the nipple. Most patients with normal physiologic
gynecomastia can be readily identified, and no further evaluation is required. If the condition does
not resolve with observation, if it is progressive or of rapid onset, or if history and examination
suggest a general medical disorder, then an underlying pathologic process should be sought.
REFERENCES
1. Braunstein GD. Gynecomastia. N Engl J Med 2007;357(12):1229–1237.
2. Dickson A. Gynecomastia. Am Fam Physician 2012;85(7):716–722.
3. Eckman A, Dobs A. Drug-induced gynecomastia. Expert Opin Drug Saf 2008;7(6):691–702.
4. Lawrence SE, Faught KA, Vethamuthu J, Lawson ML. Beneficial effects of raloxifene and tamoxifen in
the treatment of pubertal gynecomastia. J Pediatr 2004;145(1):71–76.
5. Derkacz M, Chmiel-Perzynska I, Nowakowski A. Gynecomastia—a difficult diagnostic problem.
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