Gout

Gout is an inborn error of purine metabolism characterized by

Hyperuricemia
Recurrent episodes of acute arthritis

Definition

Gout is a crystal deposition arthropathy associated with the presence of sodium monourate crystals within the neutrophils of synovial fluid associated with an inflammatory arthropathy
Derived from Latin “Gutta” = ”a drop” which means a manevolent humor dropping into weakened joints
Diagnosis confirmed by crystals of Monosodium Urate in synovial fluid
Other features

Tophi ("Porous stone") = urate in soft tissues
Renal urate stones

Epidemiology

Adult men

M:F – 20:1

Peak 40-60 years
Family History

Physiology

Prerequisite is hyperuricaemia at some stage
Uric acid level determined by balance between production & excretion

Production
- Produced by breakdown of nucleic acids
- By oxidation of Purine bases (Guanine & Adenine)
- Converted Inosine » Hypoxanthine » Xanthine » Uric Acid
- enzyme that allows the production of xanthine is Xanthine Oxidase
Excretion
- 2/3 excreted into urine
  - Uric Acid filtered at glomerulus
  - Reabsorbed in PCT
  - Secreted in subsequent PCT

1/3 excreted into GIT

Asymptomatic Hyperuricaemia

Elevated serum urate in absence of sequelae of hyperuricaemia
- Ie. absence of gouty arthritis, renal stones, tophi
Defined by serum urate levels
- Greater than 7mg/dL in men & postmenopausal women
- 6mg/dL in premenopausal women
Nil treatment required

Classification

Primary gout - 95%
- Inheritable disorder (usually idiopathic)
  - Overproducers ~ 10%
  - Underexcretors ~ 90%
Secondary gout - 5%
- Acquired disorder
  - Also caused by excessive purine load or underexcretion
Primary gout 95%
- Hyperuricaemia due to inheritable error of metabolism
- Overproducers ~ 10%
  - Due to disturbance of purine biosynthesis
    - Defined as producing more than 600mg of uric acid per 24 hours after 5 days of dietary purine restriction

Most of the conditions are polygenic or X-linked in nature
Usually idiopathic
Some specific enzyme defects known
- Hypoxanthineguanine phosphoribosyl transferase deficiency (HGPRT)
  - Lesch-Nylan Syndrome

Phosphoribosyl Pyrophosphate Synthetase overactivity
Increased production of Ribose-5-phosphate

Underexcretors ~ 90%
- Make up the majority of the patients with primary gout
- Due to abnormal renal excretion of uric acid
  - Generally they eliminate less than 350mg of uric acid per 24 hours
  - Renal excretion dependent on
    - GFR
    - Tubular resorption
    - Tubular secretion

Any one of these three or all can be implicated

Secondary Gout 5%
- Due to other acquired disorders
- Overproduction or Underexcretion
- Causes include
  - Ingestion of foods high in purine
  - High cell death/ DNA breakdown
    - Myeloproliferative disease following chemotherapy
    - Chronic haemolysis

Drugs that ↑ tubular resorption of uric acid
- Diuretics
- Salicylates
Renal failure
Acidosis
- Ketoacidosis (starvation)
- Lactic acidosis
Acute alcoholism
Obesity

*Lesch-Nyhan Syndrome

Rare
X-linked Recessive
Absence of enzyme in purine pathway
Leads to excessive uric acid formation & gout
Young boys
Retardation
Self-mutilation

Pathogenesis

Acute Gouty Arthritis

Sustained hyperuricaemia
- Develop monosodium urate monohydrate deposits in synovial lining cells & in cartilage on proteoglycans which are inert
Subsequently released into synovial fluid & connective tissue
- Precipitates at > 8mg/dL
- Due to
  - Proteoglycan turnover
  - Trauma
  - Low pH
  - Unequal resorption of water & urate from synovial fluid
Sufficient number of crystals in joint precipitates acute inflammation
- Crystals cause an inflammatory response
- Rapid ↑ in PMN
  - Phagocytosis of crystals
  - Cells then degraded due to failure of metabolism of the crystals
  - Subsequent release of the lysosomal enzymes & toxic substances
    - Proteases incl Collagenase
    - Free radicals
    - PG
    - Leukotriene

Activate complement & platelets
Disrupt lysosomes in leukocytes with cell rupture

Chronic Gouty Arthritis

Tophi (Greek = “chalk stone”) of Monosodium Urate Monohydrate Crystal
- Composed of nodular core of monosodium urate crystals with surrounding granulomatous reaction with foreign body giant cells

Very similar to rheumatoid nodules

Aggregates deposited in synovium, cartilage & tendon sheaths
Leads to cartilage destruction & periarticular cyst formation
May ulcerate through the skin

Clinical Features

"Obese, rubicund, hypertensive & fond of alcohol"

4 stages
- Initial asymptomatic hyperuricaemia
- First attack of Acute Gouty Arthritis
  - When this settles, hyperuricaemia persists

Recurrent attacks
- Frequency of attacks varies, may increase
Chronic Gouty Arthritis develops
- With joints no longer recovering from acute attacks
- Arthritis & tophi develop

Hyperuricaemia
- In men begins at puberty
- In women starts at menopause
- Only 5% of hyperuricaemic patients develop gout
Risk of Gout ↑ with
- Serum Urate Level
- Duration of hyperuricaemia
- Usually develops after 20-30 years
Acute Gouty Arthritis
- Predominantly affects distal LL
  - 70% initially 1st MTPJ (Podagra)

May also involve
- Other joints in foot
- AJ
- Knee
- Elbow
- Hands
Usually monoarticular
Rapid onset
- Excruciating night pain
- Hot red shiny swollen joint
- Very painful to touch
May have systemic features
- Fever
- Leukocytosis
- Raised ESR
Takes days/ weeks to resolve
Pain-free intervals of variable length
Onset may be spontaneous or
May be precipitated by
- Excessive activity
- Trauma
- Diet excess
- Alcohol consumption
- Diuretics
- Systemic illness or infection
- Surgery

Chronic Gouty Arthritis
- Arthritis
  - After repeated attacks of gout
    - 17% get chronic tophaceous gout 3-14 years after initial attack
    - Degree & duration of hyperuricemia reflects rate of crystal deposition

Asymmetrical destructive arthropathy
- Articular erosions
- Deformity
Often involves small joints in hand

Tophi
- In 20% of cases
- White mass of sodium urate crystals
  - Visible underlying thinned-out skin
  - May necrose overlying skin & discharge

Involve
- Synovium
- Subchondral bone
- Periarticular subcutaneous tissue
- Olecranon, Archilles, & Prepatellar bursae
- Helix of ear (actually uncommon)
Renal Stones
- 15% of cases
- Radiolucent uric acid stones
- Secondary CRF

Investigations

Laboratory Tests

Leucocytosis, elevated ESR & CRP may be seen

Serum Uric Acid
- Attacks of gout occur when levels of Serum Uric Acid changes
  - Not necessary to have ↑ level during acute attack
  - Elevated urate in patient with painful joint not diagnostic of gout

Elevated Serum Urate should be estimated in inter-critical period

Synovial fluid

Specimen must be anticoagulated
Monosodium Urate crystals diagnostic if found in synovial fluid
- Needle-shaped, yellow crystals 10um long
- Lying free or in neutrophils
- Negative birefringent*
  - Under polarized light & 1st order red compensator
  - Bright yellow when parallel to compensator
Doesn't exclude another arthropathy

Especially as infection precipitates urate

Synovial fluid analysis typically shows

WCC of 1000-70 000 x 10.6/ L
With predominantly neutrophils (< 70%)

*Birefringence
- Positive birefringence
  - Blue with crystal parallel to 1st order red compensator & 135° to polarizer
  - Yellow with crystal parallel to 1st order red compensator & 45° to polarizer
- Negative birefringence
  - Yellow with crystal parallel to 1st order red filter & 135° to polarizer
  - Blue with crystal parallel to 1st order red filter & 45° to polarizer

24 Hour Urinary Uric Acid Secretion
1100mg/day
- 50% chance renal stones
- Hence need Allopurinol

XRay

Changes with Chronic Gouty Arthritis

Usually in feet in phalangeal heads
Characteristic periarticular bony defects

Punched out lytic appearance
Overhanging sclerotic margin (Martell’s sign)

Also joint space narrowing & secondary Osteoarthritis
No osteopenia as compared with RA

Differential Diagnosis

Septic arthritis
Pseudogout
Acute bursitis
Cellulitis
RA
Osteoarthritis
Seronegative spondyloarthropathy

Management

Acute Attack

General
- RICE
- Analgesia
  - Often narcotic
Colchicine
- Inhibits activation of inflammatory mediators by crystals
- Very effective & rapid response strongly diagnostic
- 1mg then 0.5mg q2h
  - Continue until
    - Patient improves
    - Diarrhoea occur
    - Maximum 6mg reached

80% of patients unable to tolerate optimum dose because of GIT side-effects

NSAID
- Usually better tolerated than colchicine
- Indomethacin (Indocid) most commonly used
  - 50mg tds
  - Side effects include
    - GIT toxicity
    - Sodium retention
    - CNS disturbance

Naproxen & Piroxicam also effective
- Less side effects

ACTH
- Adrenocorticotrophic Hormone
- Better for acute attack with minimal side effects
- Single 40 IU Intramuscular injection
Glucocorticoids
- Oral Prednisone where
  - Colchicine not tolerated
  - NSAID contraindicated (peptic ulcer disease)

Intra-articular steroids may be used
- For severe monoarticular attack
- Especially knee

Prophylaxis

Likelihood of recurrence can be reduced by
- Weight loss
- Adequate fluid intake
- Avoid precipitating factors
  - Alcohol
  - Diuretics

Prophylactic Colchicine 1-2mg/ day
Antihyperuricaemics
- Absolute indication
  - CRF due to stones
- Relative indications
  - 3 acute attacks/ year
  - Polyarticular gout
  - Tophi
  - Uric Acid > 500mmol/L
Use drugs that
- Decrease Uric Acid Synthesis
  - Allopurinol
- Increase Renal Uric Acid Excretion
  - Uricosuric agents
  - Probenecid, Sulfapyrazole
  - Need good renal function
  - No history of renal stone
  - Lowers serum urate in 80% patients

Allopurinol
- Inhibits Xanthine Oxidase
- Blocks conversion of Xanthine to uric acid
- 300mg/ day (150mg/ day if CRF)
- Hypersensitivity side effects in 20%
  - Rash
  - Alopecia
  - Marrow suppression
  - Hepatitis
    - Can be fatal

Causes ↓ in Serum Urate
This may precipitate acute attack of gout
- Should not cease when patient already taking Allopurinol
  - Alteration to Serum Urate levels can precipitate attack

Should not commence treatment with Allopurinol during acute episode

Initiation should be accompanied by Colchicine or NSAIDS
Can shrink tophi if keep serum urate < 0.4mmol/ L

Approach

3 tier
- 1st Stage
  - Weight loss
  - Decrease purine intake
  - Fluid hydration
  - Reverse ↓ GFR
- 2nd Stage
  - Indocid
    - 50mg tds
  - or Colchicine
    - 1mg increasing 0.5mg q2h until
      - Improved
      - Diarrhoea
      - Reach 6mg
- 3rd Stage
  - If stones/ tophi/ chronic arthropathy
  - Or greater than 3 attacks

Allopurinol
- 300mg od
- Beware hypersensitivity & marrow effects

Health Quality Initiative by

Western Hospital

Sunshine Hospital

Williamstown Hospital

Gout

Definition

Epidemiology

Physiology

Asymptomatic Hyperuricaemia

Classification

*Lesch-Nyhan Syndrome

Pathogenesis

Acute Gouty Arthritis

Chronic Gouty Arthritis

Clinical Features

Investigations

Laboratory Tests

XRay

Differential Diagnosis

Management

Acute Attack

Prophylaxis

Approach