1. Definition and epidemiology
2. Purine metabolism and pathogenesis of hyperuricemia
3. Types and causes: primary vs secondary gout
4. Acute gouty arthritis: clinical features and differential diagnosis
5. Chronic tophaceous gout and renal manifestations
6. Investigations, especially synovial-fluid crystal analysis
7. Treatment of an acute attack
8. Long-term urate-lowering therapy: allopurinol, febuxostat, uricosurics
9. Lifestyle measures and prevention
10. Exam-focused short notes, tables, and viva questions

1. Complete gout note
2. Pathogenesis and causes
3. Clinical features and diagnosis
4. Acute and chronic treatment
5. Exam revision: tables, mnemonics, viva

Gout: Complete MBBS Medicine Exam Note

Definition

Epidemiology and risk factors

• More common in men, usually middle-aged or older.
• In women, incidence rises after menopause because estrogen has a uricosuric effect.
• Associated with:
  • Obesity and metabolic syndrome
  • Hypertension
  • Chronic kidney disease
  • Type 2 diabetes mellitus
  • Alcohol intake, especially beer and spirits
  • Purine-rich diet
  • Fructose-containing sweetened beverages
  • Family history
  • Drugs such as thiazide and loop diuretics, low-dose aspirin, cyclosporine, tacrolimus, pyrazinamide, ethambutol, and niacin.

Pathogenesis

Normal uric acid metabolism

• Uric acid is the final product of purine metabolism in humans.
• Humans lack uricase, which would otherwise convert uric acid into the more soluble allantoin.
• Urate is mainly eliminated by the kidney, with a smaller intestinal contribution.
• Hyperuricemia occurs due to:
  1. Decreased renal excretion, the commonest mechanism.
  2. Increased production of uric acid.
  3. A combination of both.

Mechanism of acute inflammation

1. Persistent hyperuricemia causes supersaturation of body fluids.
2. MSU crystals form and deposit in cartilage, synovium, tendons, bursae, and soft tissues.
3. A precipitating event causes shedding or exposure of crystals.
4. Crystals are phagocytosed by macrophages and activate the NLRP3 inflammasome.
5. This promotes release of IL-1 beta, TNF-alpha, and other inflammatory mediators.
6. Neutrophils enter the joint, producing the severe inflammatory attack.

Etiology of hyperuricemia

A. Primary gout

1. Decreased urate excretion

• Idiopathic renal underexcretion, most common
• Genetic variation in renal urate transporters

2. Increased urate production

• Increased activity of phosphoribosyl pyrophosphate synthetase
• Partial deficiency of hypoxanthine-guanine phosphoribosyltransferase, HGPRT deficiency
• Excess dietary purine intake

B. Secondary gout

1. Increased uric acid production

• Myeloproliferative neoplasms
• Leukemia and lymphoma
• Hemolytic anemia
• Psoriasis
• Tumor lysis syndrome
• Cytotoxic chemotherapy
• Glycogen storage disease type I
• Excess alcohol intake
• High purine diet
• Fructose-rich drinks

2. Decreased renal urate excretion

• Chronic kidney disease
• Dehydration
• Lactic acidosis
• Ketoacidosis
• Lead nephropathy, also called saturnine gout
• Diuretics, especially thiazides and loop diuretics
• Low-dose aspirin
• Cyclosporine and tacrolimus
• Pyrazinamide, ethambutol
• Nicotinic acid

Clinical stages of gout

1. Asymptomatic hyperuricemia

• Serum urate is elevated but there has been no clinical attack.
• Do not routinely treat asymptomatic hyperuricemia with urate-lowering therapy.

2. Acute gouty arthritis

Typical presentation

• Sudden onset, usually overnight.
• Severe pain, swelling, erythema, warmth, and exquisite tenderness.
• Peaks within 12 to 24 hours.
• Often monoarticular initially.
• May be associated with fever, malaise, leukocytosis, and raised inflammatory markers.

Classic site

Other common sites

• Midfoot
• Ankle
• Knee
• Wrist
• Fingers
• Elbow
• Olecranon bursa
• Achilles tendon

Precipitating factors

• Alcohol binge
• Heavy meat or seafood meal
• Dehydration or fasting
• Trauma or surgery
• Acute illness
• Diuretic use
• Initiation or dose change of urate-lowering therapy
• Rapid fall in serum urate

Natural course

3. Intercritical gout

• Symptom-free interval between acute attacks.
• MSU crystals may still be present in joints even when asymptomatic.
• Recurrent attacks become more frequent and may become polyarticular if untreated.

4. Chronic tophaceous gout

Tophi

• Helix of ear
• Olecranon bursa
• Fingers and hands
• Toes
• Achilles tendon
• Prepatellar bursa

Consequences

• Chronic inflammatory polyarthritis
• Joint deformity
• Bone erosions
• Tendon dysfunction or rupture
• Carpal tunnel syndrome
• Disability

Renal manifestations

1. Uric acid nephrolithiasis
   • Radiolucent uric acid stones
   • May cause renal colic or obstruction
   • Favoured by acidic urine
2. Acute uric acid nephropathy
   • Seen with massive urate production, especially tumour lysis syndrome
   • Urate crystal precipitation within tubules can cause acute kidney injury
3. Chronic urate nephropathy
   • Chronic interstitial deposition of urate crystals
   • Its independent role in CKD is less certain than traditionally taught

Investigations

1. Synovial fluid examination: gold standard

• Needle-shaped MSU crystals
• Strongly negatively birefringent under compensated polarized light microscopy
• Crystals may be present within neutrophils
• Inflammatory fluid with raised leukocyte count

2. Serum urate

• Often raised, but may be normal during an acute attack.
• A normal serum urate during a flare does not exclude gout.
• Measure again after the acute episode has settled.
• Used to monitor long-term treatment.

3. Blood tests

• CBC: leukocytosis may occur
• ESR and CRP: often elevated
• Renal function: serum creatinine, eGFR
• Liver function tests before or during drug therapy
• Blood glucose and lipid profile for associated metabolic disease

4. Imaging

Plain radiograph

• Juxta-articular erosions
• Overhanging edges
• “Rat-bite” or punched-out erosions
• Preserved joint space until late disease
• Soft tissue tophi

Ultrasound

• Double-contour sign due to urate deposition over articular cartilage
• Tophi may be seen

Dual-energy CT

• Can identify and quantify urate deposits.
• Helpful when aspiration is not feasible or diagnosis remains uncertain.

Differential diagnosis

Crystal comparison: very important viva table

Diagnosis

• First attack
• Atypical joint/site
• Fever or severe systemic symptoms
• Immunocompromised patient
• Prosthetic joint
• Suspicion of septic arthritis
• Poor response to treatment

Management

Principles

1. Treat the acute inflammation rapidly.
2. Look for and manage triggers and comorbidities.
3. Do not confuse treatment of a flare with lowering urate.
4. Use long-term urate-lowering therapy, ULT, when indicated.
5. Prevent flares during initiation of ULT.

A. Management of acute gout attack

General measures

• Rest the affected joint.
• Apply local ice packs.
• Ensure hydration.
• Stop avoidable precipitants, such as excess alcohol.
• Aspirate the joint if diagnosis is uncertain or infection is possible.

First-line drug options

1. NSAIDs

• Naproxen
• Indomethacin
• Ibuprofen

• CKD
• Peptic ulcer disease or GI bleeding
• Anticoagulant use
• Heart failure
• Uncontrolled hypertension
• Significant cardiovascular disease

2. Colchicine

• 1.2 mg orally initially, followed by
• 0.6 mg one hour later

• Nausea, vomiting, diarrhea
• Myopathy and neuropathy
• Bone marrow suppression with toxicity

• Severe renal or hepatic impairment
• Concurrent strong CYP3A4 or P-glycoprotein inhibitors, such as clarithromycin
• Patients receiving certain interacting drugs, including cyclosporine

3. Glucocorticoids

• Oral prednisolone, often 30 to 50 mg/day initially with short taper based on response
• Intra-articular steroid for one or few joints, after excluding infection
• Intramuscular or intravenous therapy may be used in selected severe cases

4. IL-1 inhibitors

• Anakinra or canakinumab can be considered in refractory attacks or when standard therapies are contraindicated.
• This is specialist-directed treatment and not routine MBBS-level first-line therapy.

Important point about allopurinol during acute attack

• Do not stop allopurinol in a patient already taking it during an acute flare.
• If ULT is indicated, it may be started during a flare if adequate anti-inflammatory treatment is given, though many exam answers state to initiate after the acute inflammation improves. Follow local clinical guidance.

B. Indications for urate-lowering therapy, ULT

• Two or more gout attacks per year
• Tophaceous gout
• Chronic gouty arthritis or radiographic gouty damage
• Uric acid stones
• CKD stage 3 or worse with gout
• Very high serum urate, for example above 9 mg/dL
• Recurrent, severe, disabling, or polyarticular attacks

C. Long-term urate-lowering therapy

Treatment target

• Serum urate less than 6 mg/dL in most patients
• Serum urate less than 5 mg/dL in severe tophaceous gout

1. Xanthine oxidase inhibitors

Allopurinol: first-line drug

• Start low, commonly 100 mg/day.
• Use a lower starting dose, such as 50 mg/day, in significant CKD.
• Titrate gradually every 2 to 6 weeks to serum urate target.
• Do not assume 300 mg/day is always enough.

• Rash
• GI upset
• Hepatotoxicity
• Leukopenia
• Severe allopurinol hypersensitivity syndrome: fever, eosinophilia, hepatitis, renal failure, Stevens-Johnson syndrome or toxic epidermal necrolysis

• Reduces metabolism of azathioprine and 6-mercaptopurine. Their doses must be greatly reduced or an alternative chosen.

Febuxostat

• Alternative if allopurinol is not tolerated or contraindicated.
• Start low, commonly 40 mg/day, then titrate.
• Monitor liver function.
• Use caution in patients with established cardiovascular disease because cardiovascular safety concerns have been reported in some studies.

2. Uricosuric agents

Probenecid

• Underexcretion of urate
• Good renal function
• No history of uric acid stones

• CKD
• Urolithiasis
• Marked hyperuricosuria

• Maintain adequate hydration.
• Urine alkalinization may be used in selected patients to reduce stone risk.

3. Uricase therapy

Pegloticase

• Intravenous recombinant uricase.
• Converts uric acid to soluble allantoin.
• Reserved for severe refractory chronic tophaceous gout not controlled with standard oral therapy.
• Requires specialist monitoring because infusion reactions and immunogenicity can occur.

D. Flare prophylaxis during ULT initiation

• Low-dose colchicine, commonly 0.6 mg once or twice daily if renal function permits
• Alternatively, a low-dose NSAID with gastroprotection where appropriate
• Low-dose steroid only if other options cannot be used

Lifestyle and patient education

• Gradual weight reduction if overweight
• Regular exercise
• Adequate fluid intake
• Avoid binge alcohol intake, especially beer and spirits
• Limit red meat, organ meats, shellfish, and certain oily fish
• Avoid sugar-sweetened drinks and excess fructose
• Prefer low-fat dairy products, vegetables, whole grains, and coffee if otherwise suitable
• Control hypertension, diabetes, obesity, dyslipidemia, and CKD
• Review diuretics and other hyperuricemia-inducing medications where feasible

Complications

• Recurrent painful flares
• Chronic gouty arthritis
• Joint destruction and deformity
• Tophi with ulceration or infection
• Tendon damage
• Carpal tunnel syndrome
• Uric acid nephrolithiasis
• CKD and medication-related complications
• Cardiometabolic disease association

Exam-focused short answer

Define podagra.

What is the gold-standard test for gout?

Why can serum uric acid be normal during an acute attack?

Name three first-line treatments for acute gout.

1. NSAID
2. Colchicine
3. Glucocorticoid

Name two xanthine oxidase inhibitors.

1. Allopurinol
2. Febuxostat

Indications for allopurinol or other ULT.

• Frequent attacks
• Tophi
• Radiographic joint damage
• Urolithiasis
• CKD with gout
• Severe hyperuricemia or disabling disease

Mnemonics

GOUT crystals: “N for Needle, N for Negative”

• Needle-shaped
• Negative birefringence

Acute gout treatment: “NIC”

• NSAID
• Intra-articular or systemic steroid
• Colchicine

Causes of secondary gout: “DUMP”

• Diuretics
• Urate overproduction: tumour lysis, myeloproliferative states
• Metabolic and renal disease: CKD, ketoacidosis, lactic acidosis
• Purine excess and alcohol

One-minute answer for viva