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Harrison’s Manual of Medicine






Clinical Manifestations


Definition and Pathogenesis

Clinical Manifestations

Hydroxyapatite Arthropathy
Calcium Oxalate Deposition Disease

The term gout is applied to a spectrum of manifestations that may occur singly or in combination. Hyperuricemia is the biologic hallmark of gout. When present, plasma and extracellular fluids become supersaturated with uric acid, which, under the right conditions, may crystallize and result in clinical gout.
Uric acid is the end product of purine nucleotide degradation; its production is closely linked to pathways of purine metabolism, with the intracellular concentration of 5-phosphoribosyl-1-pyrophosphate (PRPP) being the major determinant of the rate of uric acid biosynthesis. Uric acid is excreted primarily by the kidney through mechanisms of glomerular filtration, tubular secretion, and reabsorption. Hyperuricemia may thus arise in a wide range of settings that cause overproduction or reduced excretion of uric acid or a combination of the two (Table 347-2, p. 2269, HPIM-15).
ACUTE GOUTY ARTHRITIS   Monosodium urate (MSU) crystals present in the joint are phagocytosed by leukocytes; release of inflammatory mediators and lysosomal enzymes leads to recruitment of additional phagocytes into the joint and to synovial inflammation.
Clinical Manifestations

Acute inflammatory arthritis. Usually an exquisitely painful monarthritis but may be polyarticular and accompanied by fever; podagra (attack in the great toe) is the site of first attack in half and may occur eventually in 90%. Attack will generally subside spontaneously after days to weeks. Although some pts may have a single attack, 75% have a second attack within 2 years. Differential diagnosis includes septic arthritis, reactive arthritis, calcium pyrophosphate deposition (CPPD) disease, rheumatoid arthritis.


Chronic tophaceous arthritis. Tophi: aggregates of MSU crystals surrounded by a giant cell inflammatory reaction. Occurs in the setting of long-standing gout.

Extraarticular tophi. Often occur in olecranon bursa, helix and anthelix of ears, ulnar surface of forearm, Achilles tendon.

Urate nephrosis. Deposition of MSU crystals in interstitium and pyramids. Can cause chronic renal insufficiency.

Acute uric acid nephropathy. Reversible cause of acute renal failure due to precipitation of urate in the tubules; pts receiving cytotoxic treatment for neoplastic disease are at risk.

Uric acid nephrolithiasis. Responsible for 10% of renal stones in U.S.

Synovial fluid analysis—only definitive method of diagnosing gouty arthritis is joint aspiration and demonstration of characteristic needle-shaped negatively birefringent MSU crystals by polarizing microscopy. Gram stain and culture should be performed on all fluid to rule out infection.

Serum uric acid—normal levels do not rule out gout.

Urine uric acid—excretion of >800 mg/d on regular diet in the absence of drugs suggests overproduction.

Screening for risk factors—renal insufficiency, hyperlipidemia, diabetes.

If overproduction is suspected, measurement of erythrocyte HGPRT and PRPP levels may be indicated.

Joint x-rays—may demonstrate erosions late in disease.

If renal stones suggested; abdominal flat plate (stones often radiolucent), possibly IVP.

Chemical analysis of renal stones.

Asymptomatic Hyperuricemia As only about ~5% of hyperuricemic pts develop gout, treatment of asymptomatic hyperuricemia is not indicated. Exception is pts about to receive cytotoxic therapy for neoplasms.
Acute Gouty Arthritis Treatment is given for symptomatic relief only as attack is self-limited and will resolve spontaneously. Toxicity of therapy must be considered in each pt.


NSAIDs—Rx of choice when not contraindicated.

Colchicine—generally only effective within first 24 h of attack; overdose has potentially life-threatening side effects; use is contraindicated in pts with renal insufficiency, cytopenias, LFTs > 2× normal, sepsis. PO— 0.6 mg qh until pt improves, has GI side effects, or maximal dose of 5 mg is reached. IV—dangerous and best avoided; if used, give no more than 2 mg over 24 h and no further drug for 7 days following; IV must never be given in a pt who has received PO colchicine.

Intraarticular glucocorticoids—septic arthritis must be ruled out prior to injection.

Systemic glucocorticoids—brief taper may be considered in pts with a polyarticular gouty attack for whom other modalities are contraindicated and where articular or systemic infection has been ruled out.
Uric Acid–Lowering Agents Indications for initiating uric acid–lowering therapy include recurrent frequent acute gouty arthritis, polyarticular gouty arthritis, tophaceous gout, renal stones, cytotoxic therapy prophylaxis. Should not start during an attack. Initiation can precipitate an acute flare; consider concomitant PO colchicine 0.6 mg qd until uric acid <5.0 mg/dL, then discontinue.

Allopurinol: Decreases uric acid synthesis by inhibiting xanthine oxidase. Must be dose-reduced in renal insufficiency. Has significant side effects and drug interactions.

Uricosuric drugs (probenecid, sulfinpyrazone): Increases uric acid excretion by inhibiting its tubular reabsorption; ineffective in renal insufficiency; should not be used in these settings: age >60, renal stones, tophi, increased urinary uric acid excretion, cytotoxic therapy prophylaxis.

Definition and Pathogenesis
CPPD disease is characterized by acute and chronic inflammatory joint disease, usually affecting older individuals. The knee and other large joints most commonly affected. Calcium deposits in articular cartilage (chondrocalcinosis) may be seen radiographically; these are not always associated with symptoms.
CPPD may be hereditary; idiopathic, associated chiefly with aging; or occur secondary to hyperparathyroidism, hemochromatosis, hypophosphatasia, hypomagnesemia, hypothyroidism, gout, ochronosis, joint trauma, severe medical illness, or surgery.
Crystals are not thought to form in synovial fluid but probably are shed from articular cartilage into joint space where they are phagocytosed by neutrophils and incite an inflammatory response.
Clinical Manifestations
Acute “pseudogout”—occurs in ~25% of pts with CPPD disease; knee is most frequently involved, but other joints may be affected; involved joint is erythematous, swollen, warm, and painful; most pts have evidence of chondrocalcinosis. A minority will have involvement of multiple joints.
Degenerative CPPD disease—chronic arthropathy with progressive degenerative changes in multiple joints. Common sites include knee, wrist, MCP, hips, and shoulders. These pts may also have intermittent acute attacks.

Made by demonstration of calcium pyrophosphate dihydrate crystals (appearing as short blunt rods, rhomboids, and cuboids with weak positive birefringence) in synovial fluid.

Radiographs may demonstrate chondrocalcinosis and degenerative changes (joint space narrowing, subchondral sclerosis/cysts).

Secondary causes of CPPD should be considered in pts <50 years.
DIFFERENTIAL DIAGNOSIS   OA, RA, gout, septic arthritis.



Intraarticular injection of glucocorticoids

Colchicine is variably effective.

Calcium hydroxyapatite (HA) deposition can cause a calcific bursitis or tendinitis and arthropathy primarily affecting the shoulder and knee. Abnormal HA accumulation can occur idiopathically or secondary to tissue damage, hypercalcemia, hyperparathyroidism, or chronic renal failure. HA is an important factor in Milwaukee shoulder, a destructive arthropathy of the elderly that occurs in the shoulders and knees. HA crystals are small; clumps may stain purplish on Wright’s stain and bright red with alizarin red S. Definitive identification requires electron microscopy or x-ray diffraction studies. Radiographic appearance resembles CPPD disease. Treatment: NSAIDs, repeated aspiration, and rest of affected joint.
CaOx crystals may be deposited in joints in primary oxalosis (rare) or secondary oxalosis (a complication of end-stage renal disease). Clinical syndrome similar to gout and CPPD disease. Treatment: marginally effective.

For a more detailed discussion, see Wortmann RL: Disorders of Purine and Pyrimidine Metabolism, Chap. 347, p. 2268; and Reginato AJ: Gout and Other Crystal Arthropathies, Chap. 322, p. 1994, in HPIM-15.


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