A 60YearOld Woman With Generalized Weakness and Stiff Knees Chapter 21

1
A 60-Year-Old Woman With Generalized Weakness and
Stiff Knees Chapter 21
Eugene G. Martin, Ph.D. Associate Professor of
Pathology Laboratory Medicine

• Based upon LABORATORY MEDICINE CASEBOOK. An
  introduction to clinical reasoning
• Jana Raskova, MD Professor of Pathology
  Laboratory MedicineStephen Shea, MD
  Professor of Pathology Laboratory
  MedicineFrederick Skvara, MD Associate
  Professor of Pathology Laboratory MedicineNagy
  Mikhail, MD Assistant Professor of Pathology
  Laboratory MedicineUMDNJ-Robert Wood Johnson
  Medical SchoolPiscataway, NJ

2
History and Presentation

• A 60-year-old woman admitted to hospital with
  complaints of
• Generalized weakness of two weeks duration
• Morning stiffness of both knees aggravated by
  movement
• Mild fever
• Ten pound weight loss in previous month
• Two similar episodes reported in the previous
  year involving joints of wrist and hands
  responded to anti-inflammatory medications
• She has been taking aspirin to relieve the pain

• Physical Exam
• Alert ?, mild distress
• Temp. 100 oF
• BP 120/80
• HR 85 bpm and regular
• Respiratory rate 20 per minute
• Abdomen soft with mild splenomegaly
• Knees swolled, warm and painful.
• Mild atrophy of the muscles of the forearm
• Small subcutaneous nodues in the back of the
  forearms
• Swelling noted metacarpal-phalangeal joints

Whats In Your Differential? What Do You Do
Next?
3
HEMATOLOGY
4
Erythrocyte Sedimentation Rate

• PRINCIPLE The distance the erythrocytes will
  fall is a function of weight, surface area and
  charge
• Erythrocytes have a negative potential charge
  (the zeta potential) which normally repels rbcs
• Plasma proteins have a positive charge and
  promote erythrocyte aggregation. particularly
  fibrinogen
• LIMITATIONS OF TEST
• Very non-specific
• Sometimes normal where usually it is abnormal
• Very technique specific eg tilt of the tube is
  CRITICAL. Must be perfectly vertical.
• ESR falsely elevated in
• Anemia
• Macrocytosis
• Concentration of anti-coagulant too high
• ESR falsely reduced in
• Polycythemia
• Microcytosis
• Marked poikilocytosis (sickle cells,
  acanthocytes)
• Any delay in running the test (rbcs become less
  spherical and less readily form a rouleaux

5
Erythrocyte Sedimentation Rate (2)

• Conditions resulting in increased ESR
• Acute or chronic infection
• Tissue necrosis and/or infarction
• Well-established malignancy
• Rheumatoid-collagen diseases
• Temporal arteritis
• Polymyalgia rheumatica
• Rheumatoid arthritis
• Collagen disease
• Abnormal serum proteins
• Changes in serum proteins that alter plasma
  viscosity influence RBC sedimentation eg.
  Myeloma proteins
• Physiologic stress pregnancy obesity chronic
  renal failure (75)
• MARKED ELEVATIONS IN ESR
• Multiple myeloma
• macroglobulinemia
• polyclonal hypergammaglobulinemia
• hyperfibrinogenemia
• PROGNOSTIC in Hodgkins
• Poor - ESR gt60 mm/hour in asymptomatic Hodgkins
  patient (as bad as a symptomatic patient)

6
C-Reactive Protein

• Produced by the liver - present during episodes
  of acute inflammation.
• Elevations in
• Rheumatoid arthritis
• Rheumatic fever
• Cancer
• Tuberculosis
• Pneumococcal pneumonia
• Myocardial infarction
• SLE
• Connective tissue disease
• Bacterial, viral, fungal, or parastic infection
• Other causes of ongoing inflammation
• Positive CRP results also occur during the last
  half of pregnancy or with the use of oral
  contraceptives

7
CHEMISTRY
8
Rheumatoid Arthritis Lab Studies

• Anemia in approximately 80 of patients with RA.
  The anemia is normocytic and normochromic.
• Thrombocytosis may be present.
• Erythrocyte sedimentation rate (ESR) is elevated
  in approximately 90 of patients with RA.
• Serum RF result is positive in approximately 70
  of patients with RA.
• Antinuclear antibodies (ANA) are present in
  approximately 30 of patients with RA.
• Uric acid - Asprin blocks reabsorption of uric
  acid by the kidneys to a greater extent than it
  blocks secretion ? ? Uric acid. The level of uric
  acid in the blood fluctuates in response to diet,
  fluid intake, overall health status, and other
  factors.
• Felty syndrome is a triad of RA, neutropenia, and
  splenomegaly. Patients with Felty syndrome are
  prone to serious bacterial infections that result
  in higher rates of morbidity and mortality than
  for other patients with RA. This requires prompt
  diagnosis and initiation of antibiotic therapy

9
Hypoalbuminemia

• Causes of decreased plasma albumin
• Decreased synthesis.
• Increased catabolism very slow
• Increased loss
• Nephrotic syndrome
• Exudative loss in burns
• Haemorrhage
• Gut loss
• Redistribution
• Haemodilution
• Increased capillary permeability (leakage into
  the interstitium)
• Decreased lymph clearance.
• Stress response
• Overall, the picture in the stress response is
• Initial decrease in albumin associated with
  increase in acute phase proteins.
• Subsequent global increase in hepatic protein
  synthesis including albumin.

10
Patient Summary

• Hematology
• Anemia normochromic, normocytic
• Thrombocytosis
• Slightly elevated WBC
• Increased ESR
• Chemistry
• Uric Acid is a llittle low
• Albumin is a little low
• Cholesterol is a little high

11
Immunology Tests
Rheumatoid Factor (RF) usually an IgM
auto-antibody to IgG. Occasionally the antibody
is against IgA or IgE. Produced by activated B
cells and forms an immune complex by binding to
the Fc fraction of IgG molecules.
12

• Ulnar deviation of fingers
• Periarticular osteoporosis clearing at the ends
  of the bones
• Phalangeal-metacarpal joints are destroyed with
  resultant joint narrowing

13
Joint aspiration Papanicolaou stain. Mag x78.

• Knee joint aspirate
• Predominant cells -neutrophils, but scattered
  macrophages also present
• Early involvement associated with neutrophil rich
  aspirate

14
Rheumatoid Arthritis

• DESCRIPTION
• Chronic, systemic inflammatory disorder effecting
  many tissues and organs principally joints
• Cause unknown, but autoimmunity plays a pivotal
  role
• 1 of the worlds population
• PATHOGENESIS
• RA is triggered by exposure to an arthritogenic
  microbial antigen ? acute arthritis FOLLOWED by a
  runaway autoimmune reaction
• Four elements
• Genetic susceptibility
• Concordance monozygotic twins
• gt70 are HLA-DR4
• Microbial antigens
• Autoimmunity
• Mediators of joint damage (cytokines, IL, TNF,
  proteases, elastases, etc.

• MORPHOLOGY
• Joints
• Perivascular inflammatory infiltrate
• Increased vascularity
• Organizing fibrin
• Osteoclastic acitivity ?Juxta-articular erosions
• Subchondral cysts
• Osteoporosis
• Skin
• Rheumatoid nodules (25 of patients) at areas
  subject to pressure (elbows, lumbosacral)
• Blood Vessels
• Complication of severe RA
• Vasculitic syndromes potentially catastrophic
• Medium Small arteries
• Similar to Polyarteritis Nodosa EXCEPT kidneys
  ARE NOT involved
• Peripheral neuropathy, ulcers and gangrene

15
Rheumatoid Arthritis

• Joint capsule - lined with synovium, ? produces
  synovial fluid that lubricates and nourishes
  joint tissues.
• In rheumatoid arthritis, the synovium becomes
  inflamed, causing warmth, redness, swelling, and
  pain.
• The inflamed synovium invades and damages the
  cartilage and bone of the joint.
• Rheumatoid arthritis also can cause more
  generalized bone loss that may lead to
  osteoporosis

http//www.niams.nih.gov/hi/topics/arthritis/rahan
dout.htm
16
Features of Rheumatoid Arthritis

• Tender, warm, swollen joints
• Symmetrical pattern of affected joints
• Joint inflammation
• Primary - the wrist and finger joints closest to
  the hand
• Secondary - sometimes g other joints, including
  the neck, shoulders, elbows, hips, knees, ankles,
  and feet
• Fatigue, occasional fevers, a general sense of
  not feeling well
• Pain and stiffness lasting for more than 30
  minutes in the morning or after a long rest
• Symptoms that last for many years
• Variability of symptoms among people with the
  disease

17
Rheumatoid Arthritis

• Onset 20-45
• Females gt males (31)
• Associated laboratory findings
• Anemia.
• Osteoporosis
• Particularly if using corticosteroid drugs, such
  as prednisone.
• Sjogrens syndrome
• Systemic inflammatory disorder that affects the
  mucous membranes
• causing dry mouth,
• decreased tear production, and other dry
  conditions of the bodys membranes.
• Felty syndrome
• Felty's Syndrome
• Rheumatoid arthritis, Splenomegaly, Leucopoenia
  (weight loss, skin pigmentation and ulceration,
  lymphadenopathy and anaemia)

18
Normal synovial lining HE x78
Synovial Lining

• Lining epithelium is thin and lies on top of a
  loose connective tissue layer.
• Scattered lymphocytes and plasma cells are
  present
• Slightly prominent capillaries are unusual and
  may indicate that this is not a normal synovium

Loose connective tissue
19
Portion of synovium from patient. HE x 12.

• Synovial villi are thickened with a heavy
  inflammatory cell infiltrate and increased
  vascularity (granulation tissue)
• Superficial areas of necrosis are present and
  masses of inflammatory cells can be seen free
  above the synovial surface

20
Portion of synovium from patient. HE x78.

• Neutrophils, lymphocytes, plasma cells,
  macrophages, and fibroblasts are responsible for
  increased cellularity.
• Capillaries are increased in number, synovial
  lining cells are hypertophic and hyperplastic.

Hyperplastic, hypertrophic synovial lining cells
21
Material from subcutaneous nodules Unstained
DIC microscopy. Orig. mag x150

• Numerous flat, notched plates consistent with a
  cholesterol crystals.
• Common in rheumatoid nodules
• Not generally found in joint aspirates

22
Subcutaneous nodules in rheumatoid arthritis. HE
x20.

• 20-30 of patients with rheumatoid arthritis have
  rheumatoid nodules
• Most common pressure areas such as elbow
• Other locations
• Lung, spleen, myocardium, cardiac valves,
  pericardium and aorta.
• Eosinophilic center of fibrinoid necrosis
  surrounded by palisading histocytes.
• Note inflammatory cell infiltrate of lymphocytes
  and plasma cells, as well as some fibrosis.

23
Case Summary

• Final Diagnosis
• Active rheumatoid arthritis
• Symmetrical joint pain, swelling and morning
  stiffness typically

24
Sequelae of Rheumatoid Arthritis

• Higher risk of coronary heart disease
• More silent heart attacks (5X ?) and sudden
  cardiac deaths (3X ?)
• Not explained by risk factors such as elevated
  cholesterol, blood pressure and body mass index,
  diabetes, and/or alcohol abuse

25
Rheumatoid Arthritis - Differential

• Cardiomyopathy, Dilated Cardiomyopathy,
  Restrictive Carpal Tunnel Syndrome Cauda Equina
  Syndrome Conjunctivitis Corneal Ulceration and
  Ulcerative Keratitis Costochondritis
  Endocarditis Gout and Pseudogout Hepatitis
  Inflammatory Bowel Disease Iritis and Uveitis
  Myocarditis Myopathies

• Pericarditis and Cardiac Tamponade Polymyalgia
  Rheumatica Polymyositis Psoriasis Reiter
  Syndrome Sarcoidosis Scleritis Serum Sickness
  Sjogren Syndrome Systemic Lupus Erythematosus
  Temporal Arteritis Temporomandibular Joint
  Syndrome Tendonitis Tenosynovitis

http//www.emedicine.com/EMERG/topic48.htm