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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2664_Библиотеки_им_академика_М_И_Перельмана
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USMLE Step 2 CK
l Internal Medicine
National Institutes of Health
Figure 2-17. Pheochromocytoma
Differential Diagnosis. The differential diagnosis of pheochromocytoma includes essential
hypertension, anxiety attacks, factitious crisis, intracranial lesions, and autonomic epilepsy.
Management. Alpha-adrenergic blockade, phentolamine, and/or phenoxybenzamine, is
required to control BP and prevent a hypertensive crisis, since high circulating catecholamine
levels stimulate alpha receptors on blood vessels and cause vasoconstriction.
• Beta blockers are used if significant tachycardia occurs after alpha blockade; beta
blockers are not administered until adequate alpha blockade has been established,
since unopposed alpha-adrenergic receptor stimulation can precipitate a hypertensive
crisis.
• Noncardioselective beta blockers (propranolol, nadolol) are the usual choice, though
cardioselective agents (atenolol, metoprolol) may be used.
• Labetalol has been associated with paradoxic episodes of hypertension thought to be
secondary to incomplete alpha blockade.
Curative surgical removal of the pheochromocytoma is performed only after BP has been
stabilized; during surgery, IV phentolamine—a rapid-acting alpha-adrenergic antagonist—is
used for controlling BP.
DISEASES OF THE TESTES, HYPOGONADISM
In hypogonadism there is decreased function of the testes or ovaries, resulting in the absence
or impairment of secondary sexual characteristics and infertility.
Etiology
• Primary hypogonadism (hypergonadotropic: increased LH, FSH) can result from
Klinefelter syndrome (small testes, eunuchoid, 47XXY), anorchia, surgical or accidental castration or radiotherapy, infections (mumps, TB, leprosy), or chemotherapeutic agents.
• Secondary hypogonadism (hypogonadotropic: low LH, FSH) can result from hypopituitarism secondary to idiopathic causes or tumors, hypothalamic lesions, and Kallmann
syndrome (hypogonadic hypogonadism, associated with decreased sense of smell).
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Chapter 2
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l Endocrinology
Clinical Findings. Clinical findings include prepubertal hypogonadism, most often caused
by a specific gonadotropic deficiency of the pituitary. External genitalia are underdeveloped,
voice is high-pitched, beard does not grow, and the patient lacks libido and potency. As an
adult, the patient has a youthful appearance, with obesity, disproportionately long extremities,
lack of temporal recession of the hairline, and a small Adam’s apple. Gynecomastia is sometimes seen. The skin is fine-grained, wrinkled, and free of acne. The testes may be absent from
the scrotum. Bone age is retarded. Urinary 17-ketosteroid is low to normal, and serum testosterone is below normal. Serum FSH and LH are low in hypothalamic or pituitary origin and
elevated in primary testicular failure. Treatment is with testosterone.
Klinefelter syndrome is the most common primary developmental abnormality causing hypogonadism (testicular damage). This syndrome affects 1 of every 400–500 males. It is caused by
one or more supernumerary X chromosomes. Eighty percent of patients have a 47,XXY karyotype. Gynecomastia is found with elevated levels of LH and FSH. Sterility and lack of libido are
present. The testes are small and thin. Mental retardation may be present. Urinary 17-ketosteroids are low normal or normal, serum testosterone is low to normal, LH and FSH are elevated,
and serum estradiol is elevated. Treatment is testosterone replacement.
Answers
Following are the answers for Table 2-2 seen earlier.
Evaluating Thyroid Function
Note
Males affected by Klinefelter
syndrome have a 20×
increased risk of breast
cancer.
Thyroid Hormones and TSH RAI Uptake Scan Diagnosis
↓ TSH; free ↑ T4, ↑ T
3
↑ RAIU De novo synthesis of hormone
(primary hyperthyroidism)
↓ TSH; free ↑ T4, ↑ T
3
↓ RAIU Factitious hyperthyroidism or
inflammation or destruction of
the gland releasing preformed
hormone into the circulation
(subacute thyroiditis)
↓ TSH; free ↓ T4, ↓ T
3
↓ RAIU Secondary or tertiary
hypothyroidism
51
Rheumatology
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Chapter Title
Learning Objectives
❏ List the steps for evaluating a patient with arthritis
❏ Differentiate between autoimmune arthritis, seronegative arthritis, osteoarthritis,
crystal-induced arthritis, and septic arthritis
❏ Differentiate and describe the treatment approaches to rheumatoid arthritis, systemic
lupus erythematosus, drug-induced lupus, scleroderma, Sjögren syndrome
❏ Differentiate and describe treatment approaches to seronegative arthropathies,
including ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and entero-
pathic arthritis
❏ Answer questions about the management of osteoarthritis, crystal-induced
arthropathies, and septic arthritis
00
3
❏ Describe the diagnosis and management of vasculitis syndromes and inflammatory
myopathies
EVALUATING A PATIENT WITH ARTHRITIS
When a patient presents with joint swelling, a differential diagnosis is generated based on the
answers to the following questions:
1. What is the distribution of joint involvement and how many joints are involved?
Polyarticular symmetric involvement is characteristically seen with rheumatoid arthritis (RA),
systemic lupus erythematosus (SLE), parvovirus B19, and hepatitis B. On the other hand,
monoarticular arthritis is consistent with osteoarthritis, crystal-induced arthritis (gout, pseudogout), septic arthritis (gonococcus), trauma, and hemarthrosis.
Migratory arthropathy (inflammation and pain migrates from joint to joint, while the previous involved joints improve) is caused by rheumatic fever, disseminated gonococcal infection,
and Lyme disease. Oligoarticular asymmetric arthritis is common with the spondyloarthropathies (ankylosing spondylitis) and osteoarthritis involving the small joint of the upper
extremities and rarely as a presentation of polyarticular gout.
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USMLE Step 2 CK
l Internal Medicine
2. Are the symptoms acute or chronic?
Osteoarthritis is a chronic disease; the patients have symptoms for months to years. Patients
with septic arthritis or crystal-induced arthropathies have short-lived symptoms, commonly
only a few days.
3. Does the patient have systemic symptoms (beyond the arthritis)?
SLE presents with lung (pleural effusions), kidney (proteinuria and renal failure), CNS (vasculitis, strokes, and change in personality), skin (malar and photosensitivity rash), and hematologic (immune-mediated anemia, thrombocytopenia) manifestations.
Sjögren syndrome has keratoconjunctivitis sicca (dry eyes/mouth) and parotid enlargement.
Systemic sclerosis has skin involvement and Raynaud phenomenon.
Wegener granulomatosis presents with upper respiratory (sinusitis and rhinitis), lower respiratory (lung nodules and hemoptysis), and renal (necrotizing glomerulonephritis) involvement.
OA, on the other hand, presents with absence of systemic symptoms.
4. Is there evidence of joint inflammation?
Evidence of joint inflammation includes: joint stiffness in the morning >1 hour, joint erythema
and warmth, and elevated erythrocyte sedimentation rate (ESR) and C-reactive protein. An example of inflammatory arthritis is rheumatoid arthritis, while OA is typically noninflammatory.
Do not go further into a history unless you have answered the above 4 questions.
Examples
• A 62-year-old man presents with right knee pain.
• A 24-year-old woman presents with bilateral wrist, MCP, PIP joint swelling, and pain.
• A 32-year-old man presents with knee swelling after you had seen him one week ago
for left wrist pain and swelling, which has now resolved.
• A 29-year-old man has right knee pain and swelling and left hip pain.
TESTS IN RHEUMATOLOGIC DISEASES
Joint Aspiration
If there is fluid in the joint, it needs analysis immediately.
The basic tests to run on the synovial fluid are the 3 Cs (cell count, crystals, and cultures) and
the Gram stain.
Synovial fluid may be stratified according to the number of cells:
• OA and traumatic arthritis have 200–2,000 WBCs/mm3 in the synovial fluid
• Inflammatory diseases (RA, gout) have 5,000–50,000 WBC/mm
• Septic arthritis has >50,000 WBC/mm
3
3
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Table 3-1. Synovial Fluid Analysis in Different Rheumatologic Diseases
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Disease WBCs Crystals/Polarization
DJD <2,000 Negative
traumatic
Inflammatory 5,000–50,000 Gout: needle-shaped, negative
birefringent
Pseudogout (CPPD): Rhomboid-shaped,
positive birefringent
Septic >50,000 Negative (Gram stain and culture
usually negative for GC but positive in
Staph, strep, and gram-negatives)
There are a few exceptions to the above:
• Septic arthritis may sometimes present with <50,000 WBC/mm3 in the joint aspirate
if antibiotics are given before the joint aspiration. Septic arthritis should be considered
a possibility in a patient with >5,000 WBC/mm3 in the synovial fluid, monoarticular
arthritis, but absence of crystals.
• Gout and pseudogout uncommonly present with >50,000 WBC/mm3 in the absence
of infection. Consider this possibility if there is evidence of crystals in the aspirate.
• Culture of joint fluid is positive in only 50% or less of gonococcal arthritis.
Chapter 3
l Rheumatology
Antinuclear Antibodies
Antinuclear antibodies (ANA) are antibodies that have the capability of binding to certain
structures within the nucleus of the cells. ANAs are found in patients whose immune system
may be predisposed to generate antibodies against their own body tissues. This is referred to
as autoimmunity.
Although ANAs are found in patients with SLE, Sjögren syndrome, and systemic sclerosis,
they may also be found in approximately 5% of normal people. When ANAs are present in
normal people, they are usually in low titers (<1:80).
The ANA test is performed by exposing the antibodies in the serum of the blood to the laboratory test cells. It is then determined whether or not antibodies are present that react with
various parts of the nucleus. Fluorescent techniques are now more frequently used, thus the
test may be referred to as a fluorescent antinuclear antibody test (FANA).
ANAs present in different patterns depending on the staining of the cell nucleus: homogeneous, speckled, nucleolar, and peripheral (or rim). While these patterns are not specific
for any one disease, certain diseases can more frequently be associated with one pattern or
another. For example, the peripheral (rim) pattern may be seen with SLE, while the nucleolar
pattern is more commonly seen in systemic sclerosis. The speckled pattern is more commonly
seen in normal people.
Also, subsets of ANAs are associated with specific autoimmune diseases and are thus used to
further diagnose these diseases. For example, anti ds-DNA and anti-SM antibodies are found
in patients with SLE; anti-histone antibodies are found in patients with drug-induced lupus.
(See Tables 3-2 and 3-3.)
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USMLE Step 2 CK
l Internal Medicine
Table 3-2. ANA Patterns
Peripheral (Rim) SLE
Diffuse Nonspecific
Clinical Correlate
Overall, >95% of SLE patients
have positive ANA test results,
which makes a negative ANA
result a good rule-out test for
SLE.
Interpret a positive ANA test
in the context of the clinical
symptoms, i.e., a positive ANA
in an asymptomatic patient
with no other abnormal tests
is likely to be a false–positive
(5% of the population); a
positive ANA in a patient
with arthritis, proteinuria, and
pleural effusion is likely to be
associated with SLE.
Speckled Nonspecific
Centromere CREST
Nucleolar Systemic sclerosis
Table 3-3. Specific ANAs
Anti-ds-DNA (native DNA) SLE only (60%); an indicator of disease activity
and lupus nephritis
Anti-SM SLE only (25–30%)
Anti-histone Drug-induced lupus (95%)
Anti-Ro (SSA) Neonatal lupus, Sjögren and in the 3%
of ANA-negative lupus
Anti-LA (SSB) Sjögren
Anti-centromere CREST
Anti-RNP 100% mixed connective tissue disease (MCTD)
Rheumatoid Factor
Rheumatoid factor (RF) is an autoantibody against the Fc portion of IgG. Rheumatoid factors
are found in approximately 70% of patients with RA. However, these antibodies are not specific for RA and are found in 5% of healthy adults (the prevalence increases with age, sometimes seen in up to 20% of people >65 years of age).
56
Therefore, RF is neither sensitive nor specific for the diagnosis of RA.
The presence of RF can be of prognostic significance, since patients with high titers tend to
have more aggressive disease with extraarticular manifestations.
Antineutrophil Cytoplasmic Antibodies
Antineutrophil cytoplasmic antibodies (ANCAs) are antibodies directed against certain proteins in the cytoplasm of neutrophils. The cytoplasmic (c) ANCA refers to the diffuse staining
pattern observed when serum antibodies bind to indicator neutrophils; it is seen in >90% of
patients with Wegener granulomatosis. Perinuclear (p) ANCA refers to a localized staining
pattern observed on the indicator neutrophils, the major target of these antibodies being the
enzyme myeloperoxidase; it is found in PAN and Churg-Strauss but is a nonspecific test.
Antiphospholipid Antibody Syndrome
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Antiphospholipid antibody syndrome (lupus anticoagulant or anticardiolipin antibodies) is a
hypercoagulable state associated with a group of antibodies that are directed against phospholipids or cardiolipins. It is unclear whether the antibodies are directly involved in the etiology of
the clotting disorder associated with this syndrome. The nature of these antibodies causes the
common laboratory abnormalities associated with the syndrome, i.e., elevated partial thromboplastin time (PTT) and false-positive RPR or VDRL. Clinically, it presents with spontaneous
abortions in otherwise healthy women or thromboembolism (pulmonary embolism, DVT) in
other patients. Two first-trimester spontaneous abortions suggest antiphosolipid antibodies.
RHEUMATOID ARTHRITIS
A 26-year-old woman with no prior medical history presents with a 3-week history of
joint swelling and stiffness. She informs you that she has had stiffness for about
2 h every morning since these symptoms started and that the symptoms improve as
the day progresses. She denies back stiffness or back pain. She has fatigue and lowgrade fever. On the examination the wrist, MCPs, and PIPs are red and swollen on
both hands. The DIPs are not involved. There is fluid in the wrist joints. Otherwise the
examination is normal.
Chapter 3
l Rheumatology
Definition. RA is a chronic inflammatory multisystemic disease with the main target being
the synovium. The hallmark of RA is inflammatory synovitis that presents in a symmetric
distribution. The intense joint inflammation that occurs has the potential to destroy cartilage
and cause bone erosions and eventually deform the joint.
Anti-CCP (cyclic citrullinated peptide) is also positive in RA and carries a very high specificity.
Etiology/Epidemiology. The cause of RA is unknown. RA may be triggered as a reaction to an
infectious agent (mycoplasma, parvovirus) in a susceptible host.
Of the environmental factors, only cigarette smoking seems to be associated with RA.
Women are affected 3× more than men, and in 80% of cases the age of onset is between 35
and 50 years.
Pathogenesis. An initiation phase of nonspecific inflammation occurs, followed by an amplification phase resulting from T-cell activation, and finally the stage of chronic inflammation
and tissue injury.
The predominant infiltrating cell is the T lymphocyte. Diseases like human immunodeficiency virus (HIV), in which T cells are decreased, will characteristically improve preexisting RA;
this is also the reason why RA is very rare in patients with HIV.
Recent studies have shown that excessive amounts of the pro-inflammatory cytokines—tumor
necrosis factor alpha (TNF-a), interleukin-1, and interleukin-6 (IL-6)—mediate most of the
pathogenic features of rheumatoid arthritis. This underscores the focus of new treatment
modalities on inhibiting these cytokines (see TNF inhibitors on following pages).
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USMLE Step 2 CK
l Internal Medicine
Presentation. Diagnostic criteria—need 4 of the following diagnostic criteria.
• Morning stiffness (>1 h) for 6 weeks
• Swelling of wrists, MCPs, PIPs for 6 weeks
• Swelling of 3 joints for 6 weeks
• Symmetric joint swelling for 6 weeks
• RF positive or anti-cyclic citrullinated peptide
• CRP or ESR
X-ray abnormalities and nodules are not necessary for the diagnosis of RA.
Criteria. RA is a chronic inflammatory symmetric arthropathy. There needs to be involvement of multiple joints, but some joints are never involved in RA:
• DIPs
• Joints of the lower back
Note
In 2010, a new set of criteria
was proposed by the American
College of Rheumatology and
the European League against
Rheumatism which focuses
more on serologies, acute
phase reactants, number of
joints involved, and duration of
joint involvement over 6 weeks.
This leads to a point system.
For the moment, the 1987
criteria are not obsolete.
Because RA is a systemic disease, ~70% of patients present with constitutional symptoms—
fatigue, anorexia, weight loss, generalized weakness—before the onset of the arthritis.
Extraarticular Manifestations
• Damage to the ligaments and tendons
– Radial deviation of the wrist with ulnar deviation of the digits
– Boutonnière deformity
– Swan-neck deformity
• Rheumatoid nodules
– Initial event caused by focal vasculitis
– 20–30% of patients with RA; usually occur in areas of mechanical stress
(olecranon, occiput, Achilles tendon)
– Methotrexate may flare this process
• Felty syndrome (RA + splenomegaly + neutropenia)
• Caplan syndrome (RA + pneumoconiosis)
Laboratory Findings
• RF or anti-CCP
• Anemia
• ESR or C-reactive protein (CRP)
• X-rays
• Synovial fluid analysis
58
Diagnosis. The diagnosis is based on the use of clinical criteria; there is no single test or finding that will diagnose RA. Anti-CCP is more specific than RF.
Treatment. None of the nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to
be better than aspirin in RA, but they have fewer GI side effects.
There is no single NSAID superior to other agents, and the newer agents have not been shown
to have a decreased incidence in toxicity (GI, renal, etc.).
Cyclooxygenase 2 (COX-2) inhibitors are a type of NSAID which selectively blocks the COX-2
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enzyme at the site of inflammation. The benefit of COX-2 inhibitors is that they do not inhibit COX-1, an enzyme that helps with the production of the protective stomach lining. The
nonselective (traditional) types of NSAIDs block both COX-2 and COX-1, which can lead to
increased risk for GI side effects (bleeding, etc.).
Because of the increased risk of MI, both rofecoxib and valdecoxib have been recalled; currently only celecoxib is available.
Other drugs in RA:
• Glucocorticoids (usually for short courses only)
• Disease-modifying agents: antimalarials, gold, sulfasalazine, methotrexate (MTX), and
tumor necrosis factor (TNF) receptor inhibitors
Disease-Modifying Anti-Rheumatic Drugs
The best initial DMARD is methotrexate (MTX). If MTX does not control disease, an antiTNF medication is added to treatment.
Chapter 3
l Rheumatology
Table 3-4. Adverse Effects of DMARD
Drug Profile/Side Effects Screening Tests for Toxicity
Hydroxychloroquine Retinopathy Regular eye examination
MTX (methotrexate; most
utilized agent and mainstay of treatment)
Hydroxychloroquine and sulfasalazine are used in early, mild disease. Steroids are used briefly
to control disease while waiting for methotrexate to work.
Biologic Agents. Tumor necrosis factor (TNF) inhibitors. Tumor necrosis factor alpha (TNF-
) is a pro-inflammatory cytokine produced by macrophages and lymphocytes. It is found in
large quantities in the rheumatoid joint and is produced locally in the joint by synovial macrophages and lymphocytes infiltrating the joint synovium. TNF inhibitors relieve the signs
and symptoms of RA, and slow or halt radiographic damage. These drugs have been shown
be effective in patients who were thought to be resistant to all methotrexate.
Latent assessment and treatment for TB is required before use of any of these agents.
There are 3 TNF inhibitors approved for the treatment of RA:
• Infliximab (Remicade) is a monoclonal antibody to TNF-α that binds to TNF-α in the
joint and in the circulation. The combination of infliximab and methotrexate is very
effective in reducing clinical manifestations of disease. Infliximab is given as an IV
infusion. Cases of sepsis, disseminated tuberculosis, and other opportunistic infections
have been reported for patients treated with infliximab or other anti-TNF therapy.
• Adalimumab (Humira) is an anti-TNF mAb that differs from infliximab in that its
sequences are entirely human.
• Etanercept (Enbrel) is a human fusion protein that is entirely human, and anti-etanercept antibodies are relatively uncommon.
Rapid onset of action;
hepatitis and hepatic
fibrosis; pneumonitis; may
flare rheumatoid nodules
CBC and liver enzymes every
4–8 weeks
to
Note
Screen for TB before using
TNF inhibitors.
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