Crystalinduced Arthropathy: Gout and Pseudogout

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Crystal-induced ArthropathyGout and Pseudogout

• Michael J. Battistone, MD
• Musculoskeletal Organ Systems
• November 21, 2005

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Objectives-I

• Identify and describe
• asymptomatic hyperuricemia
• acute gouty arthritis
• intercritical gout
• chronic tophaceous gout
• Recognize risk factors for hyperuricemia and
  gout, including major disease associations

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Objectives-II

• Be familiar with basic principles in diagnosis
• synovial fluid WBC count/differential
• polarizing microscopy
• Be familiar with basic principles of treatment of
  gout and calcium pyrophosphate deposition disease

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Lecture Overview-I

• Gout
• definitions and clinical manifestations
• pathophysiology
• metabolic steps leading to uric acid
• renal excretion of uric acid
• acute gouty arthritis
• precipitating factors
• diagnosis
• treatment options

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Lecture Overview-II

• Gout (contd)
• intercritical gout
• chronic tophaceous gout
• clinical features
• diagnosis
• treatment options

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Lecture Overview-III

• Calcium pyrophosphate deposition disease (CPPD,
  or pseudogout)
• definitions
• clinical features
• diagnosis
• treatment options
• Sample questions
• Your questions

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Key Points-I

• Hyperuricemia increases risk of gout, but
  hyperuricemia alone is not gout
• Predisposing factors for gout
• other diseases (associated with hyperuricemia)
• medications
• environmental conditions
• Several diseases associated with CPPD
• Estrogen is uricosuric

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Key Points-II

• Properties of monosodium urate crystals
• needle-shaped, negatively birefringent
• Properties of calcium pyrophosphate crystals
• rhomboid, positively birefringent
• Allopurinol should never be used as treatment for
  acute gouty arthritis, nor given to someone who
  is also taking azathioprine

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Gout Definitions

• Gout is a disease characterized by hyperuricemia
  and monosodium urate deposition in the body
• Gouty arthritis is joint inflammation caused by
  monosodium urate crystals in the synovial fluid
  and/or joint tissues

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Gout Clinical Manifestations

• Acute gouty arthritis
• Intercritical gout
• Chronic tophaceous gout
• Miscellaneous other (e.g., gouty nephropathy)

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Uric Acid BalanceChoi et al. Pathogenesis of
gout. Annals Intern Med 2005 143499
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Gout Pathophysiology

• Uric acid overproduction vs. underexcretion
• Mechanisms of urate production
• cellular nucleoproteins/nucleotides ( 66)
• diet (33)
• Mechanisms of urate excretion
• kidney (66)
• gut (33)

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Renal Excretion of Uric Acid

• Completely filtered by the glomerulus
• Completely (essentially) reabsorbed in the
  proximal tubule
• Approximately 50 is secreted back into the
  tubule in the descending loop
• Approximately 80 (of the 50 now in the loop) is
  reabsorbed in the ascending loop
• Net excretion 10 of filtered load

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Urate Excretion

• hOAT3- human renal organic anion transporter
• hUAT1
• hUAT2
• URAT 1

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OAT

• OAT
• URAT1-
• mutations implicated in familial renal
  hypouricemia
• Proximal tubule
• Suppressed by uricosurics and losartan, high
  dose salicylate
• Lasix may increase its fxn

Bieber JD et al. Gout-On the Brink of Novel
Therapeutic Options for an Ancient Disease. 50
(8). August 2004, p2400-2414.
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Diet
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Diet
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Diet
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Diet

• 12 year prospective study of 47,150 men with no
  h/o gout
• 730 new cases of gout
• Conclusions
• High levels of meat and seafood increased risk
• High levels of dairy decreased the risk
• Moderate intake of purine-rich vegetable or
  protein not associated with increase risk of gout

Choi HK, et al. Purine-Rich Foods, Dairy and
Protein Intake, and the Risk of Gout in Men. NEJM
350(11). March 2004. 10931103.
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Asymptomatic Hyperuricemia

• Hyperuricemia alone does NOT make a diagnosis of
  gout
• -only a subset of people with hyperuricemia will
  develop gout
• -probability of gout increases with higher uric
  acid levels
• Asymptomatic hyperuricemia generally requires no
  treatment

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Conditions AssociatedWith Hyperuricemia

• Lymphomas (esp. Hodgkins disease)
• Myeloproliferative disorders
• Diabetes
• Psoriasis
• Sarcoid
• Glycogen storage disease

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Acute Gouty ArthritisClinical Features

• Acute onset (hours) of severe arthritis
• Usually monarticular
• almost any joint can be affected
• 1st MTP joint (podagra) most common (50)
• Other joints (in decreasing frequency) midfoot,
  ankle, heel, knee, wrist, fingers, elbow
• Associated findings fever, ? WBC, ? ESR
• Typically resolves over days or weeks, regardless
  of treatment

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Acute Gouty Arthritis
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Acute Gouty ArthritisPrecipitating Factors

• Surgery
• Alcohol
• Fluctuation of uric acid level
• initiation of therapy to lower uric acid level
• diuretics (esp. hydrochlorothiazide)
• aspirin
• low doses raise uric acid levels
• high doses lower uric acid levels

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Acute Gouty ArthritisDiagnosis

• Observation of monosodium urate crystals in
  synovial fluid leukocytes
• Monosodium urate crystals are
• needle-shaped
• negatively birefringent

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Negative Birefringence
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Negative Birefringence
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Acute Gouty ArthritisTreatment Options

• Non-steroidal antiinflammatory drugs
• Colchicine
• Steroids
• intra-articular
• oral
• Joint aspiration
• Analgesics
• Observation (no therapy)

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Intercritical Gout

• Symptom-free period between attacks (may be
  months or years)
• If untreated, episodes of acute gouty arthritis
  become more frequent, last longer, and often
  involve more joints (polyarticular)

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Chronic Tophaceous GoutClinical Features

• Tophi are deposits of urate crystals in tissue
• Common sites
• synovium
• subchondral bone
• olecranon bursae
• infrapatellar
• Achilles tendon

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Chronic Tophaceous GoutClinical Features

• Frequent attacks of acute gouty arthritis
• Bone destruction and degenerative arthritis are
  common in advanced cases

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Chronic Tophaceous Gout
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Chronic Tophaceous Gout
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Chronic Tophaceous Gout
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Chronic Gout-Radiographic Features
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Chronic Tophaceous GoutTreatment Options

• Control and prevent acute gouty arthritis
• Non-steroidal antiinflammatory drugs
• Colchicine
• Steroids
• Analgesics
• Reduce serum uric acid levels (
• decrease uric acid production (inhibit xanthine
  oxidase)
• increase uric acid excretion (uricosuric drugs)

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Xanthine Oxidase InhibitionAllopurinol

• Blocks conversion of hypoxanthine to xanthine,
  and xanthine to uric acid
• Accumulation of hypoxanthine inhibits de novo
  purine biosynthesis (negative feedback)
• DO NOT USE allopurinol with azathioprine or
  6-mercaptopurine

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Uricosuric AgentsProbenecid

• Blocks renal tubular resorption of uric acid
• Most effective when urine pH basic and flow
  relatively high
• Used less frequently than allopurinol

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Calcium Pyrophosphate Deposition Disease
(CPPD)Clinical Presentations

• Pseudogout
• frequent attacks after surgery, trauma
• knee most commonly involved
• Pseudo-rheumatoid arthritis
• Pseudo-osteoarthritis
• Pseudo-neuropathic joint

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CPPD Associated Diseases

• Definitely Associated
• Hemochromatosis
• Hyperparathyroidism
• Hypophosphatemia
• Hypomagnesemia
• Wilsons disease

• Possibly
• Associated
• Hypothyroidism
• Gout
• Ochronosis

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CPPD Diagnosis

• Observation of calcium pyrophosphate dihydrate
  crystals in synovial fluid leukocytes
• CPPD crystals are
• rhomboid
• positively birefringent

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What Type of Birefringence?
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What Type of Birefringence?
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What Type of Birefringence?
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CPPD-Arthroscopic View
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CPPD Radiographic Features

• General similarities to osteoarthritis
• Chondrocalcinosis--calcification of cartilage
• menisci of knees
• triangulofibrocartilage of wrists
• Other sites demonstrating calcification
• bursae
• joint capsule
• synovium
• tendon

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CPPD-Chondrocalcinosis
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CPPD Treatment Principles

• No definitive therapy for prevention
• Goals in managing acute attacks
• reduce symptoms
• identify and treat any associated or triggering
  illnesses
• encourage mobility as inflammation subsides

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CPPD Treatment Options

• Joint aspiration
• NSAIDs
• Colchicine (not as effective as for gout)
• Steroids (not as effective as for gout)
• oral
• intra-articular
• Analgesics
• Surgery if necessary to preserve function

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Question 1

• A 36-year old man develops heart failure and
  liver cirrhosis, accompanied by a progressive
  bronzing of his skin over 12 months. He comes
  to your office because his right knee has been
  swollen for a few days.
• After obtaining a complete history and physical
  exam, you aspirate the knee, obtaining some
  opaque fluid.

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Question 1-contd

• Which of the following do you expect in examining
  the fluid under a polarizing microscope?
• a. Needle-shaped crystals, with the yellow
  crystal perpendicular to the slow axis of
  compensation
• b. Rhomboid crystals, with the blue crystal
  parallel to the slow axis of compensation
• c. Chondrocalcinosis
• d. Rhomboid crystals, with the yellow crystal
  parallel to the slow axis of compensation

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Answer

• a. Needle-shaped crystals, with the yellow
  crystal perpendicular to the slow axis of
  compensation
• b. Rhomboid crystals, with the blue crystal
  parallel to the slow axis of compensation
• c. Chondrocalcinosis
• d. Rhomboid crystals, with the yellow crystal
  parallel to the slow axis of compensation

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Question 2

• Which of these patients is at the least risk for
  gout?
• a. A 50-year old man with hypertension treated
  with hydrochlorothiazide, 25 mg daily
• b. A 50-year old woman with hypothyroidism who
  takes L-thyroxine, a daily aspirin, and estrogen
  replacement
• c. A 32-year old man with psoriasis and Hodgkins
  disease
• d. A 50-year old woman whose only medication is a
  daily aspirin

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Answer

• Whom of the following is at the least risk for
  gout?
• a. A 50-year old man with hypertension treated
  with hydrochlorothiazide, 25 mg daily
• b. A 50-year old woman with hypothyroidism who
  takes L-thyroxine, a daily aspirin, and estrogen
  replacement
• c. A 32-year old man with psoriasis and Hodgkins
  disease
• d. A 50-year old woman whose only medication is a
  daily aspirin

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Question 3

• It is July. It is the first call night of your
  first clerkship (medicine!), and you are at the
  VA. Your resident misread the schedule and,
  thinking you are one of her interns, sends you to
  see a patient who has been admitted with what is
  thought to be an infected knee.
• Your patient tells you that something like this
  happened a few years ago, to my big toe. Among
  other things, you learn he is taking
  hydrochlorothiazide, aspirin, and acetaminophen
  you find that his right foot and ankle, as well
  as his knee, are swollen.

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Question 3-contd

• You easily recall the inspiring lecture on
  crystal-induced arthropathies you had during
  organ systems, and decide to tap the joint.
• This is what you see . . .

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Question 3-contd

• Which of the following would you NOT include in
  your recommendations to the resident regarding
  treatment options?
• a. Indomethacin
• b. Colchicine (orally)
• c. Colchicine (by vein)
• d. Allopurinol
• e. Prednisone

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Answer

• Which of the following would you NOT include in
  your recommendations for treatment options?
• a. Indomethacin
• b. Colchicine (orally)
• c. Colchicine (by vein)
• d. Allopurinol
• e. Prednisone

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Key Points-I

• Hyperuricemia increases risk of gout, but
  hyperuricemia alone is not gout
• Predisposing factors for gout
• other diseases (associated with hyperuricemia)
• medications
• environmental conditions
• Several diseases associated with CPPD
• Estrogen is uricosuric

64
Key Points-II

• Properties of monosodium urate crystals
• needle-shaped, negatively birefringent
• Properties of calcium pyrophosphate crystals
• rhomboid, positively birefringent
• Allopurinol should never be used as treatment for
  acute gouty arthritis, nor given to someone who
  is also taking azathioprine