NSL1 PBL3 Gout

Learning Outcomes:

 Anatomy of the bones and joints in the foot (Anna)

 Structure of the synovial joint and types - Wui Chin
 Purine metabolism and other sources of uric acid - William
 Gout
o Etiology – Shanjey
o Epidemiology – Shanjey
o Risk factors – Disura
o Pathophysiology- William
o Clinical features – Diya
o Investigations and diagnosis – Diya
o Complications – Jo
o Treatment and management – Jo
o Prevention (if any)
 Emotional and mental health issues due to gout

Structure of synovial joints and types

Components of synovial joints

 Articular capsule
o Fibrous capsule (Outer) – Fibrous – White dense connective tissue/ Envelops and
holds joint/ Area of tendinous or ligamentous attachment
o Synovial membrane (Inner) – Production of synovial fluid/ Greatest blood supply
 Articular surface + Cartilage – Hyaline cartilage/ Shock absorber/ Smooth movement/
Protect underlying bone
 Joint cavity + Synovial fluid – Shock absorber/ Lubricant/ Exchange nutrients and waste
 Supporting structures

o Articular arteries/ Veins – Production of synovial fluid/ Supply synovium most/

Extensive anastomoses
o Articular nerves (E.g. Hip - Sciatic/ Femoral/ Obturator) –
 Sensory - Proprioceptors/ Deep pressure/ Nociceptors
 Motor (Autonomic) – Vasoconstriction/ Vasodilation
o Ligaments (Intra-articular/ Extra-articular) – Between bones/ Supports joints/ Bones/
Stability
o Muscular tendons – Muscular insertion into bone/ Movement/ Stability

o Bursae – Synovial fluid-filled sac/ Minimise friction between highly mobile areas of
joints (E.g. Between tendon-bone/ tendon-tendon etc)
o Menisci – Fibrocartilage/ Shock absorbing/ Stability
Types of synovial joint

 Plane – Multiaxial/ Gliding movements/ E.g. Acromioclavicular/ Intercarpal/ Intertarsal

 Hinge – Uniaxial/ E.g. Knee/ Elbow/ Interphalangeal/ 1st metacarpophalangeal
 Pivot – Uniaxial/ Rotational movement/ E.g. Atlanto-axial joint/ Superior inferior radioulnar
joint
 Condylar/ Ellipsoid – Biaxial/ Movement between convex and concave surface/ E.g.
Radiocarpal/ Atlanto-occipital joint/ 2nd-5th metacarpophalangeal/ Metatarsophalangeal
 Saddle – Biaxial/ Movement between concave surface/ E.g. 1st carpometacarpal joint
 Ball and socket – Multiaxial/ E.g. Glenohumeral/ Acetabulofemoral
Purine metabolism pathway

 De novo synthesis – Ribose-5-phosphate (R5P)  Phosphoribosyl pyrophosphate (PRPP) 

Inositol monophosphate (IMP) 
o AMP  ATP - RNA  d(Deoxy)ATP - DNA
o GMP  GTP – RNA  dGTP – DNA

 Degradation pathway – Can be via different parts of pathway (Not all metabolites in pathway
considered purines)
o AMP  Adenosine –(Adenosine deaminase – ADA) Inosine  Hypoxanthine –
(Xanthine oxidase – XO) Xanthine –(XO) Uric acid
o IMP  Inosine  Hypoxanthine  Xanthine  Uric acid
o GMP  Guanosine  Guanine  Xanthine  Uric acid

Excreted via kidneys – Glomerular filtration  PCT reabsorption (Almost complete)  DCT secretion

 Salvage pathway
o AMP  Adenosine  Adenine –(APRT) AMP
o IMP  Inosine  Hypoxanthine –(HGPRT) IMP
o GMP  Guanosine  Guanine –(HGPRT) GMP

Clinical significance – Note areas where disease/ drugs can act to modify serum uric acid levels
RF/ Etiology/ Pathogenesis

RF (Primary gouty arthritis)

 Purine rich food

 Obesity
 Alcohol
 Chemotherapy (Tumour lysis syndrome)
 Partial HPRT enzyme deficiency (Polymorphisms)
 Thiazide/ Aspirin use
 Anaemia
 Diabetes
 Dehydration (Reduce renal clearance)

Etiology (Secondary)

 Lynch nyhan syndrome (Complete HPRT enzyme deficiency)

 CKD
 Haemolytic anaemia

All RF and causes associated hyperuricaemia

Pathogenesis

 Asymptomatic hyperuricaemia
 Increasing/ Excessive uric acid  Precipitation of monosodium urate (MSU)
 Phagocytosis of MSU + Resulting inflammatory reaction
o Neutrophil – Phagocytosis 
 Release inflammatory mediators
 Crystals cause damage to cell/ Phagolysosome  Cell death + Release of
lysosomes  Damage joints
o Macrophage – Phagocytosis  Release of inflammatory mediators

Action of inflammatory mediators in pathogenesis of gout

Recruit more immune cells  +ve feedback loop into inflammation/ Release of enzymes that lowers
pH (Increase MSU precipitation)/ Damage to joint (Via inflammatory mediators/ Lysosomes)/
Formation of granuloma (Tophi)

Pathophysiology/ Clinical features/ Complications

General – Pathophysiology associated with Deposition of MSU  Acute/ chronic inflammation 

Damage to joints/ surrounding tissues + Granuloma formation – Phase dependent
Asymptomatic hyperuricaemia – Usually no symptoms

Acute gouty arthritis (Acute inflammation + Damage)

 Most commonly 1st metatarsophalangeal joint

 Sudden acute attacks
 Night flares
 5 signs of inflammation – Localised redness/ Warmth/ Swelling/ Pain/ Lost of function
 Excruciating pain (Usually more than other joint pathologies) – Can wake you up at night
 Occur in phases (Interchange between intercritical period) – But reducing duration of
intercritical period as disease progresses/ No management of RF

Asymptomatic intercritical period (Resolution of acute inflammation + Attempted healing) –

Resolution of acute attack

Chronic tophaceous arthritis (Chronic inflammation + Granuloma formation)

 Pannus formation (Possibly palpable – Firm/ Boggy mass)

 Tophi (Granuloma) – Grossly observable/ Via imaging

Complications

 Bony/ Fibrous ankylosis

 Joint/ Bony deformity
 Reduce joint function/ Immobility
 Uric acid nephrolithiasis/ Nephropathy
Diagnosis

 Clinical signs and symptoms – (Above)

o Differentials
 Pseudogout – Hypercalcaemia/ Knee/ Rhomboid crystals/ Pathophysiology
similar to gout
 OA – Obesity/ Previous injury/ Abnormal biomechanical loading/ LOSS/
Heberden nodes/ Bouchard nodes/ Weight bearing (Hip/ Knee/ Ankle/
Vertebrae/ DIPJ)
 RA – Initial systemic chronic inflammation/ Rheumatoid factor/ Citrulinated
protein Ab/ Subcondral cyst only/ Osteoporosis/ Pannus/ Polyarthritis +
Symmetrical/ Small proximal joints or hands and feet (E.g. PIPJ)/
Extraskeletal manifestation (CVS/ Liver/ Kidney/ Brain/ Eyes/ Skin)
 Septic arthritis – Fever/ Hx trauma/ Orthopaedic procedure/ Causes of
bacteraemia
 Seronegative arthropathies – Sacroiliitis/ Dactylitis/ Enthesitis
 Psoriatic arthritis – Psoriatic plaques
 Reactive arthritis – Hx GI/ Urogenital infection (2-4 weeks ago)
 Ankylosing spondylitis – Similar RA presentation/ Schober’s test +ve/
SIJ involvement rare in RA
 Tumour – Growing mass/ Bony surface instead of joint/ Classical bone
tumour radiological findings/ Cancer cachexia/ Metastasis
 Osteomyelitis – Fever/ Bony surface instead of joint/ Sinus tract/
Sequestrum/ Involucrum/ Brood’s abscess/ Same RF for septic arthritis
 MSK injury related trauma – Hx trauma
 Fractures – Compound fracture with visible bones
 Blood test – Hyperuricaemia
 Urinalysis – Increase uric acid
 X ray –
o Non-specific sign for joint damage – Loss of joint space
o Tophi – Osteolytic lesions/ Over-hanging bones/ Sclerosis/ Radio-opaque MSU
aggregation (Chalky white deposition)
 Joint aspiration – Presence of uric acid crystals (Needle-like on microscopy)
 Criteria
Treatment

Lifestyle modifications

 Limit alcohol consumption

 Limit intake of purines
 Limit high-fructose corn syrup
 Weight loss if overweight

Acute gout

 Nonpharmacological: Rest and ice the affected joint

 Pharmacotherapy (initiate within 24 hours of onset)
o Glucocorticoids
 Systemic administration
 Oral (prednisone)
 Parenteral or intramuscular (methylprednisolone)
 Intraarticular - Consider if there are 1-2 joints that are accessible

o NSAIDs (E.g. Naproxen) - Treat for the shortest duration necessary to resolve
symptoms (3-5 days)

o Colchicine - Binds and stabilises tubulin subunits  Inhibits microtubule

polymerization  inhibits phagocytosis of urate crystals  Inhibit neutrophil
activation/ migration/ degranulation
Chronic gout

 Urate-lowering therapy
o First line: Xanthine-oxidase inhibitors (allopurinol) – Reduce uric acid production
(Degradation pathway)
o Second line: Uricosurics (probenecid) - Inhibition of uric acid reabsorption along the
renal PCT  Increased renal elimination
o Third line: Recombinant uricase (pegloticase) - Catalyses the breakdown of uric acid
to the water-soluble purine metabolite allantoin, which is then renally excreted

Anti-inflammatory prophylaxis with colchicine, NSAIDs or glucocorticoids must be administered

before initiating ULT - ULT may trigger, prolong or worsen an acute gout flare