Case 11: Richard Strong

Uric Acid: Production

Purine degradation

AMP/GMP/XMP (xanthosine monophosphate) → Nucleosides (adenosine, guanosine, xanthosine) → Xanine → Uric acid

Xanthis oxidase/dehydrogenase: Xanthine → Uric acid

Uric Acid: Excretion

Urate anion → Urine (60-70%) + GI tract (30-40%)

1. Glomerulus: Free filtration

2. PCT: Reabsorption (99%)

3. PCT: Secretion (50%)

Uric Acid: Renal Handling

Hyperurecemia from…

• Underexcretion: Most common

• Overproduction

Hyperurecemia: Underexcretion

Decreased glomerular filtration

Increased reabsorption

Decreased secretion

From:

• Diuretics

• Metabolic dysfunction (hyperinsulinemia, hypovolemia)

• Drugs (aspirin)

Hyperuricemia: Overproduction

Increased purine synthesis = Increased purine breakdown

Enzyme deficiency/defects

High cell turnover (malignancy, psoriasis)

Why don’t other mammals get gout?

Uricase (urate oxidase) enzyme convert uric acid → Allontoin = No uric acid buildup

Allontoin: More soluble substrate in urine = Increase excretion in kidneys

Gout: Description

Inflammatory crystal arthropathy

4 Stages:

1. Hyperuricemia: Asymptomatic

2. Acute Flares/Attacks: Self-limiting symptoms

3. Intercritical: Asymptomatic period between flairs

4. Chronic Tophaceous Gout: Persistent symptoms

Gout: Epidemiology

Risk factors…

• Diet (high purine)

  • Red meat

  • Seafood

  • Alcohol

  • Sweet beverages

• Drugs

  • Diuretics

  • Cyclosporins

  • ACE inhibitors

  • Beta-blockers

  • Aspirin

• Obesity

• Male

• Older age

Gout: Etiology

Hyperuricemia (> 0.4 mmol/L)

Primary: Idiopathic

Secondary:

• Decreased Excretion

  • Drugs (aspirin, loop diuretics, thiazides, niacin)

  • CKD

  • Ketoacidosis

  • Lactic acidosis

  • Post-menopause

• Increased Production

  • High cell turnover (tumor lysis syndrome, hemolytic anemia, chemo)

  • Enzyme defects

  • Purine-rich diet

  • Obesity

  • Hypercholesterolemia

• Combined Decreased Excretion + Increased Production: Alcohol consumption + lactic acid

  • Purine-rich alcohol = Alcohol metabolism products compete for excretion = Decrease uric acid excretion

Gout: Pathophysiology

1. Hyperuricemia = Uric acid crystals coated in IgG precipitate + deposit in synovial fluid

• Triggered by acidosis + low temp (peripheral joints)

2. Immune cells phagocytose IgG-covered crystals = Release inflammatory markers = Joint inflammation

3. Chronic: Repeated attacks = Urate crystals + large cells (tophi) aggregate in joint = Deformities + arthritis

Gout: Clinical Presentation

Hyperuricemia: Asymptomatic

Acute Gout Attacks:

• Severe joint pain, erythema, decreased ROM, swelling, warmth

  • At night → Wake from pain

  • Peak 12-24h + regress after

• Fever

• Joint skin desquamation (flaking) during recovery

• Joints Affected:

  • Monoarthritis

  • Asymmetrical

  • Peripheral joints

    • Podagra: Big toe MTP

    • Gonagra: Knee

    • Chiragra: Finger joints

Intercritical: Asymptomatic

Chronic Gout:

• Gouty tophi: Painless hard nodules on joints

  • Bone tophi: Crystal deposition in bones

  • Soft tissue tophi: Crystal deposition in external ear, subcutis, tendon sheaths, bursae

• Nephrolithiasis (uric acid stones)

• Nephropathy

Gout: Investigations

Arthrocentesis + synovial fluid analysis

Blood test

Imaging

Gout Investigations: Arthrocentesis + Synovial Fluid Analysis

Gold standard

Polarized light microscopy: Needle-shaped urate crystals

• Parallel optical axis = Yellow

• Perpendicular optical axis = Blue crystals

WBC > 50 000/mm³

Gram stain: Neg

• R/O septic arthritis

Gout Investigations: Blood Test

CBC

• Increased WBC + ESR

Serum uric acid

• Usually increased (> 6.8 mg/dL)

Screening:

• Creatinine → CKD

• Lipid → Dyslipidemia

• Glucose → DM

Gout Investigations: Imaging

Supportive

US:

• Joint inflammation

• Bone erosions

• Double contour sign: Hyperechoic band of crystals covering hypoechoic articular cartilage

XR:

• Acute: Normal

• Chronic:

  • Periarticular erosions: Punched-out lytic bone lesions + spiky overhanging edges

  • Radiopaque soft tissue: Swelling

Gout: General Treatment

Lifestyle changes

• Limit alcohol

• Diet changes: Limit purine-rich foods + high-sugar drinks

• Weight loss

Acute Gout: Treatment

Nonpharmacological

Pharmacological

Acute Gout Treatment: Nonpharmacological

Rest

Ice

Acute Gout Treatment: Pharmacological

Initiate ≤ 24h

NSAIDs

• Ex: Naproxen, indomethacin, ibuprofen

Glucocorticoids

• Systemic (oral, parenteral, intramuscular) or intraarticular

• Ex: Prednisone, prednisolone

Colchicine

Urate-lowering therapy (ULT)

• Ex: Xanthine oxidase inhibitors (allopurinol), uricosurics

Acute Gout Treatment: Colchicine

MOA: Inhibit microtubule polymerization = Inhibit urate crystal phagocytosis + inhibit WBC migration = Decrease inflammation

Acute Gout Treatment: ULT

Indications:

• ≥ 2 attacks/year

• Chronic gout imaging

• Tophi development

Chronic Gout: Treatment

ULT

Chronic Gout Treatment: ULT

First-line

Indications: Same as acute

Contraindications:

• Acute gout flare

• Asymptomatic hyperuricemia

Agents:

• First-Line: Xanthine oxidase inhibitors (allopurinol)

• Second-Line: Uricosurics (probenecid)

• Third-Line: Recombinant uricase (pegloticase)

Anti-Inflammatory Prophylaxis: 1 week before ULT prevent worsening symptoms

• Colchicine

• NSAIDs

• Glucocorticoids

Gout: Complications

Nephrolithiasis: Uric acid stones

Uric acid nephropathy: Stone deposition in kidney = Inflammation

• HTN

• Renal failure

Bursitis