Gout and Pseudogout

Gout — by mechanism

• Underexcretion of urate (~90%): reduced renal clearance via URAT1/GLUT9 (SLC2A9) and ABCG2 transporters. Causes include chronic kidney disease, volume depletion, lead nephropathy (saturnine gout), and drugs.
• Overproduction (~10%): increased purine turnover. Myeloproliferative/lymphoproliferative disease, tumor lysis syndrome, hemolysis, psoriasis, and enzyme defects — HGPRT deficiency (Lesch–Nyhan: self-mutilation, choreoathetosis, gout in a boy), PRPP synthetase overactivity, and glucose-6-phosphatase deficiency (von Gierke disease, where lactate also blocks urate excretion).
• Drug-induced (a favorite stem plant): thiazide and loop diuretics, low-dose aspirin, cyclosporine and tacrolimus, pyrazinamide and ethambutol, niacin, and cytotoxic chemotherapy.

Modifiable risk factors

• Diet and alcohol: purine-rich red meat and shellfish, beer and spirits (beer adds guanosine), and high-fructose beverages (fructose phosphorylation consumes ATP and generates urate).
• Metabolic: obesity, insulin resistance, metabolic syndrome, hypertension — hyperinsulinemia enhances renal urate reabsorption.
• Precipitants of a flare: dehydration, surgery, acute illness, trauma, and any abrupt shift in urate (including initiation of urate-lowering therapy).

Non-modifiable risk factors

• Male sex and age; women are largely protected until menopause because estrogen is uricosuric.
• Genetics/ancestry: urate transporter polymorphisms; *HLA-B\*58:01* does not cause gout but predicts severe allopurinol hypersensitivity, and the ACR 2020 gout guideline conditionally recommends testing it in patients of Southeast Asian or African American ancestry before starting allopurinol.

Pseudogout (CPPD)

• Age and joint injury dominate — prior meniscectomy or osteoarthritic cartilage is the substrate; chondrocalcinosis prevalence rises steeply after age 60.
• Metabolic screening is indicated in patients under ~55 or with polyarticular disease: hyperparathyroidism, hemochromatosis, hypophosphatasia, hypomagnesemia (including Gitelman syndrome), and hypothyroidism.
• Familial CPPD from ANKH mutations causes early-onset, florid chondrocalcinosis.

Gout

• Hyperuricemia (serum uric acid >6.8 mg/dL) leads to supersaturation and MSU crystal precipitation in synovial fluid, particularly in lower-temperature peripheral joints (first MTP joint most common)
• Crystals are needle-shaped and negatively birefringent under polarized light; phagocytosis by macrophages and monocytes triggers the NLRP3 inflammasome pathway
• NLRP3 activation leads to caspase-1 cleavage and excessive IL-1β and IL-18 production, driving acute neutrophilic infiltration and intense inflammation
• Risk factors for crystal formation include male sex, age, diuretic use, purine-rich diet, alcohol (especially beer), acute illness/fasting, chronic kidney disease, and genetic factors
• Triggers for acute attacks include sudden changes in uric acid levels (either rapid increases or decreases), acute illness, surgery, dehydration, and NSAIDs

Pseudogout

• Calcium pyrophosphate dihydrate (CPPD) crystals deposit in cartilage (chondrocalcinosis) and synovial fluid
• Crystals are rhomboid-shaped and positively birefringent under polarized light; also trigger NLRP3 inflammasome through phagocytosis
• Associated with hypomagnesemia, hypophosphatasia, hypothyroidism, hemochromatosis, and hyperparathyroidism (remember mnemonic: "CHOP" - Calcium, Hemochromatosis, hypOphosphatasia, Parathyroidism)
• Mechanism of crystal formation less well understood than gout; local joint trauma and aging are risk factors
• Can present as acute attacks, chronic inflammatory arthritis, or pseudo-osteoarthritis pattern

Acute Gout Attack

• Sudden-onset severe monoarticular or oligoarticular pain, typically nocturnal; first metatarsophalangeal (1st MTP) joint is classic ("podagra") but can affect ankle, knee, wrist, or elbow
• Dramatic inflammatory signs: erythema, warmth, swelling, and exquisite tenderness; joint appears almost septic clinically
• Attack typically peaks within 24-72 hours and resolves spontaneously in 7-10 days even without treatment
• Polyarticular involvement more common in recurrent attacks or chronic gout; women typically develop gout after menopause due to loss of uricosuric effect of estrogen
• Tophi (deposits of monosodium urate crystals) may appear on ear helix, fingers, elbows, or other sites in chronic tophaceous gout

Acute Pseudogout Attack

• Similar presentation to gout: acute monoarticular or oligoarticular joint pain, warmth, swelling, erythema
• Knee is most commonly affected (unlike gout's predilection for 1st MTP), followed by wrists and shoulders
• Typically affects older patients (peak age 60-80 years), and attacks are often more indolent than gout
• May see chronic chondrocalcinosis pattern (pseudo-osteoarthritis) with progressive joint damage and morning stiffness; inflammation less florid than acute attack

Important Clinical Distinctions

• Gout tends to affect younger men and lower extremities; pseudogout affects older patients and upper extremities
• Pseudogout attacks are often milder and last longer (1-2 weeks vs. 7-10 days for gout)
• Gout is more likely to have multiple recurrent attacks in untreated hyperuricemia; pseudogout is often self-limited and recurrences are less predictable

Gold Standard: Synovial Fluid Analysis

• Arthrocentesis with polarized light microscopy is definitive diagnostic test for both conditions
• Gout: negatively birefringent, needle-shaped MSU crystals inside neutrophils and free in fluid
• Pseudogout: positively birefringent, rhomboid-shaped CPPD crystals (appearance described as "haystack" or "coffee-bean" shaped)
• Cell count: typically 2,000-50,000 WBC (predominantly neutrophils); >50,000 suggests possible infectious arthritis—bacterial culture should always be sent
• Crystals may still be present between attacks and do not rule out gout/pseudogout in asymptomatic joints

Laboratory Testing

• Serum uric acid: helpful in gout but does NOT diagnose acute attack (may be falsely low during acute inflammation); check 2-4 weeks after attack resolution
• Baseline uric acid target: <6 mg/dL for most patients (below saturation point), <5 mg/dL for tophaceous gout or recurrent attacks
• Renal function, electrolytes, calcium, phosphate, magnesium: assess for secondary causes and complications
• 24-hour urine uric acid or uric acid-to-creatinine ratio: distinguish underexcretors (90% of gout) vs. overproducers (10%)

Imaging

• X-ray findings in chronic gout: punched-out lytic lesions with overhanging edges (pathognomonic), tophi visible on plain radiographs
• Ultrasound or CT: useful for detecting CPPD chondrocalcinosis; not required for acute diagnosis but helps with chronic management
• Joint imaging: assess for cartilage damage, chronic inflammatory changes in recurrent/chronic cases

Diagnostic Pearls

• Do NOT exclude gout based on normal serum uric acid during acute attack (may be falsely normal)
• Always obtain synovial fluid to confirm diagnosis; never empirically treat for gout without aspiration if diagnosis unclear
• Rule out bacterial infection (fever, very high WBC count >50,000, positive cultures) before assuming crystal arthritis

Acute Gout Attack Management

• NSAIDs (indomethacin 50 mg TID for 5-7 days, naproxen 500 mg BID, or ibuprofen 800 mg TID): most effective if started within 36-48 hours of symptom onset
• Colchicine: 1.2 mg initially, then 0.6 mg one hour later (loading dose), then 0.6 mg daily for prophylaxis; efficacy is time-dependent (best if <36 hours); caution with renal/hepatic impairment (accumulates and causes toxicity)
• Corticosteroids: 30-40 mg prednisone daily for 5-7 days, tapering (or intra-articular injection for monoarticular attacks); preferred in patients with renal insufficiency, heart failure, or contraindications to NSAIDs/colchicine; avoid abrupt discontinuation due to rebound flares
• IL-1 inhibitors (anakinra, canakinumab, rilonacept): reserved for refractory cases unresponsive to NSAIDs, colchicine, or corticosteroids

Acute Pseudogout Attack

• NSAIDs (indomethacin, naproxen) or corticosteroids (same dosing as gout)
• Colchicine: less effective than in gout but may be tried
• Intra-articular corticosteroid injection: often preferred for knee involvement due to large joint size and accessibility

Complications of the disease

• Chronic tophaceous gout: persistent supersaturation lets MSU aggregate into granulomatous tophi in the helix, olecranon bursa, and finger pads. Signal finding is punched-out erosions with overhanging sclerotic edges and preserved joint space on radiograph. Tophi can ulcerate, drain chalky material, and become secondarily infected.
• Urate nephrolithiasis and chronic urate nephropathy: radiolucent stones form in persistently acidic urine; medullary interstitial urate deposition causes slowly progressive CKD.
• Acute uric acid nephropathy: an emergency — massive purine load in tumor lysis syndrome precipitates urate in tubules, producing oliguric AKI with a urine uric acid–to–creatinine ratio above 1. Prevented with hydration and rasburicase.
• Coexistent septic arthritis: an emergency and the single most important pitfall. Crystals do not exclude infection; fever, a synovial WBC well above the crystal-arthritis range, or a positive Gram stain mandates drainage and antibiotics.
• Crowned dens syndrome (CPPD): calcification around the odontoid causes acute neck pain, fever, and elevated inflammatory markers, mimicking meningitis. CPPD also causes destructive pseudo-osteoarthritis and a symmetric pseudo-rheumatoid pattern.

Complications of treatment

• Colchicine toxicity: microtubule poisoning causes diarrhea first, then myelosuppression and proximal neuromyopathy with elevated CK. Risk soars in renal impairment and with CYP3A4/P-glycoprotein inhibitors — clarithromycin, cyclosporine, verapamil.
• Allopurinol hypersensitivity syndrome (DRESS/SJS-TEN): an emergency; rash with fever, eosinophilia, hepatitis, and AKI, tied to *HLA-B\*58:01*. Stop the drug immediately.
• Allopurinol plus azathioprine or 6-mercaptopurine: xanthine oxidase blockade causes life-threatening myelosuppression — the classic tested interaction.
• Febuxostat: FDA boxed warning for cardiovascular death; ACR 2020 favors allopurinol first-line.
• Pegloticase: anaphylaxis and, in G6PD deficiency, hemolysis and methemoglobinemia — screen before use.
• Probenecid: promotes stone formation; avoid in urate overproducers and CKD. NSAIDs cause GI bleeding and AKI; steroids cause hyperglycemia.
• ULT-initiation flare: rapid urate lowering mobilizes crystals; ACR 2020 recommends 3–6 months of anti-inflammatory prophylaxis.

• The buzzword pair: podagra with needle-shaped, negatively birefringent crystals that appear yellow when parallel to the compensator axis = gout; rhomboid, positively birefringent crystals that appear blue when parallel = pseudogout. Remember "yellow parallel = urate."
• Single best next step in any acutely hot, swollen joint is arthrocentesis with cell count, Gram stain, culture, and polarized microscopy — never a serum uric acid level. Uric acid is often normal or low during a flare because inflamed tissue takes up urate.
• The one interaction examiners love: allopurinol plus azathioprine or 6-mercaptopurine. Xanthine oxidase inhibition blocks thiopurine catabolism and causes profound pancytopenia. Reduce the thiopurine dose drastically or avoid the combination.
• Do not treat asymptomatic hyperuricemia. The ACR 2020 gout guideline conditionally recommends against urate-lowering therapy in patients with hyperuricemia alone, even at high levels.
• Do not stop urate-lowering therapy during an acute flare, and per ACR 2020 it is acceptable to start allopurinol during a flare as long as anti-inflammatory coverage is given. Treat the flare and the urate simultaneously.
• Allopurinol is first-line ULT even in CKD, started low and titrated to a serum urate target below 6 mg/dL by treat-to-target monitoring; febuxostat carries an FDA boxed warning for cardiovascular death.
• Chondrocalcinosis in a young patient is a metabolic clue — think hemochromatosis (with MCP arthropathy and hook-like osteophytes) or primary hyperparathyroidism, not primary CPPD.
• Common distractors: assuming crystals rule out infection (they do not — septic arthritis can coexist and is the emergency); calling a normal uric acid exclusionary; and stopping cardioprotective low-dose aspirin to lower urate. If an antihypertensive must change, losartan and fenofibrate are mildly uricosuric while thiazides worsen gout.