Crystal-induced Arthropathy: Gout and Pseudogout

1. Crystal-induced Arthropathy:Gout and Pseudogout Michael J. Battistone, MD Musculoskeletal Organ Systems November 21, 2005

2. 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

3. 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

4. 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

5. Lecture Overview-II • Gout (cont’d) • intercritical gout • chronic tophaceous gout • clinical features • diagnosis • treatment options

6. Lecture Overview-III • Calcium pyrophosphate deposition disease (CPPD, or “pseudogout”) • definitions • clinical features • diagnosis • treatment options • Sample questions • Your questions

7. 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

8. 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

9. 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

10. Gout: Clinical Manifestations • Acute gouty arthritis • Intercritical gout • Chronic tophaceous gout • Miscellaneous other (e.g., gouty nephropathy)

11. Uric Acid BalanceChoi et al. Pathogenesis of gout. Annals Intern Med 2005; 143:499

12. 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%)

13. 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

14. Urate Excretion • hOAT3- human renal organic anion transporter • hUAT1 • hUAT2 • URAT 1

15. 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.

16. Diet

17. Diet

18. Diet

19. 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.

20. 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

21. Conditions AssociatedWith Hyperuricemia • Lymphomas (esp. Hodgkin’s disease) • Myeloproliferative disorders • Diabetes • Psoriasis • Sarcoid • Glycogen storage disease

22. Acute Gouty Arthritis:Clinical 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

23. Acute Gouty Arthritis

24. Acute Gouty Arthritis:Precipitating 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

25. Acute Gouty Arthritis:Diagnosis • Observation of monosodium urate crystals in synovial fluid leukocytes • Monosodium urate crystals are • needle-shaped • negatively birefringent

28. Negative Birefringence

29. Negative Birefringence

30. Acute Gouty Arthritis:Treatment Options • Non-steroidal antiinflammatory drugs • Colchicine • Steroids • intra-articular • oral • Joint aspiration • Analgesics • Observation (no therapy)

31. 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)

32. Chronic Tophaceous Gout:Clinical Features • Tophi are deposits of urate crystals in tissue • Common sites: • synovium • subchondral bone • olecranon bursae • infrapatellar • Achilles tendon

33. Chronic Tophaceous Gout:Clinical Features • Frequent attacks of acute gouty arthritis • Bone destruction and degenerative arthritis are common in advanced cases

34. Chronic Tophaceous Gout

35. Chronic Tophaceous Gout

36. Chronic Tophaceous Gout

37. Chronic Gout-Radiographic Features

38. Chronic Tophaceous Gout:Treatment Options • Control and prevent acute gouty arthritis • Non-steroidal antiinflammatory drugs • Colchicine • Steroids • Analgesics • Reduce serum uric acid levels (< 4.0 mg/dL) • decrease uric acid production (inhibit xanthine oxidase) • increase uric acid excretion (uricosuric drugs)

39. Xanthine Oxidase Inhibition:Allopurinol • 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

41. Uricosuric Agents:Probenecid • Blocks renal tubular resorption of uric acid • Most effective when urine pH basic and flow relatively high • Used less frequently than allopurinol

42. 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

43. Definitely Associated Hemochromatosis Hyperparathyroidism Hypophosphatemia Hypomagnesemia Wilson’s disease Possibly Associated Hypothyroidism Gout Ochronosis CPPD: Associated Diseases

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

45. What Type of Birefringence?

46. What Type of Birefringence?

47. What Type of Birefringence?

48. CPPD-Arthroscopic View

49. 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

50. CPPD-Chondrocalcinosis