Rheumatology E-learning
University of Szeged
Department of Rheumatology and Immunology
The definition of gout
Arthritis urica: an acute inflammatory process elicited by the precipitation of uric acid cristals inside the joint or in other soft tissues
Known also in ancient times
Famous people with gout: Henry VIII, Louis XIV, Thomas Jefferson, Alfred Tennyson, Charles V (German and Spanish Emperor), Hungarian king Mathias,
„Disease of the kings”
Gouty arthritis
Acute gouty attack
Chronic tophaceous gout
The history of gout
First signs of gout: Egyptian mummies 2000 B.C.
First description: Hippokrates – podagra (pain in the foot)
1679: Leuwenhook describes the needle-shaped crystals obtained from tophi
1600s: precise description of gout by Thomas Sydenham (a gout sufferer)
1776: the first characterisation of uric acid
Early 1800s: first use of colchicum as a treatment. Colchicum autumnale: meadow saffran, a flower from the coasts of the Black Sea
1861: Alfred Garrod connects uric acid with gout
1963: introduction of allopurinol
The source of uric acid in the body
Endogenous pathway
(80%) - liver
1. Nucleic acid-breakdown
2. de novo purin-
nukleotide synthesis
Exogeous pathway (20%)
Small intestinal epithelium
(nucleotides from food)
Adenin Guanin
AMP GMP
Inosin-monophosphate (IMP)
Hypoxantin
Xantin
Uric acidXantin-
oxidase
Xantin-
oxidase
Uricase – not present in humans
The pathways of endogenous uric
acid formation
1. DNA, RNA breakdown: Nucleotides → nukleosides → AMP, GMP
Depends upon cell-turnover (tumor, psoriasis, increase in basal metabolism /stress, physical strain, infection/, fasting
2. De novo nucleotide synthesis Ribose-5-P → phosphoribosil-pirophosphate (PRPP) → IMP → AMP, GMP
PRPP synthetase (Ribose-phosphate-
pirophosphokinase) Amidophosphoribosil-transferase
3. Salvage-mechanisms AMP, GMP, IMP + phosphoribosil-pirophosphate (PRPP) → adenin, guanin
Hypoxantin-guanin-phosphoribosil-transferase (HGPRT)
Causes of hyperuricaemia
Mechanism:
Overproducers (10%)
Underexcretors (90%)
Aetiology:
Primary (10%)
Secondary (90%)
Normal serum uric acid levels:
120-360 μmol/l (2-6 mg/dl) (females)
180-420 μmol/l (3-7 mg/dl) (males)
Primary hyperuricaemias
PRPP synthetase increased activity X-linked disease
Increased production of PRPP → increased supply of adenine-and guanine nucleotide constituents
Gouty arthritic and urinary stone attacks in early adulthood
HGPRT deficiency X-linked disease
Loss of feedback inhibition of amidophosphoribosil transferase → increased de novo purin synthesis
Lesch-Nyhan syndrome – gout, mental retardation, choreo-athethosis, chronic urate nephropathy
Decreased uric acid clearance Hereditary renal tubular deficiency of unknown background
Secondary hyperuricaemias –
overproduction of uric acid
Haematological malignancies, cell destruction (trauma, cancer), cytotoxic drugs, psoriasis
Increased consumption of foods with high uric acid content (cocoa, chocolate, liver, meat, pea, lentil, beer)
Fasting
Fever, stress, infection
Alcohol (mixed aetiology) – increased purin-nucleotide synthesis, increased renal Na + uric acid reabsorption (Na-H exchange )
Obesity (mixed aetiology)
Secondary hyperuricaemias –
decreased excretion of uric acid Metabolic syndrome
Hyperinsulinism – increased Na-H exchange in the proximal tubules –increased uric acid reabsorption
Very frequent association with obesity, hypertension, diabetes, hyperlipidaemia, atherosclerosis
Acute or chronic renal insufficiency Dehydration, other causes of acute renal failure
Chronic tubulo-interstitial diseases (polycystic kidney disease, tubulo-interstitial nephritis, hyperparathyreoidism, lead intoxication)
Acidosis Alcohol, lactate acidosis, ketoacidosis… Increased Na-H exchange in the
proximal tubules – increased uric acid reabsorption
Drugs Diuretics (thiazide and furosemide)
Cyclosporin
Low dose aspirin
Hyperuricaemia and gout
Hyperuricaemia # gout
In one survey: the five-year cumulative incidence rates of gouty arthritis 2.0 percent for a serum urate level of 8.0 mg per dL
(475 µmol per L) or lower,
19.8 percent for urate levels from 9.0 to 10.0 mg per dL (535 to 595 µmol per L)
30 percent for a serum urate level higher than 10 mg per dL (595 µmol per L).
Gouty arthritis = 1) precipitation of monosodium-urate crystals + 2)inflammation
Precipitation: urate concentration , pH ↓, temperature ↓
Inflammation in gouty arthritis
Urate crystals are phagocyted by neutrophils and macrophages
Neutrophil activation: Proteases, reactive oxigen species, leukotrienes,
prostanoids
IL-1, TNF-α, IL-6
Macrophage activation: Chemokines, TNF-α, IFN-γ
Crystals activate the NALP3 inflammasome
„autoinflammatory disease”
Activation of the innate immune system
Neutrophil granulocyte „oxidative burst” –enzymes, ROI, prostaglandins
Chemokines
Inflammasome hyperactivation → IL-1βoverproduction
„Autoinflammatory syndrome”
Gout - epidemiology
Prevalence: 5/1000 in men, 2/1000 in
women
Peak incidence:
Men: 30-50 years
Women: 45-60 years
Younger age: hereditary cause
Older age: association with other diseases
(renal failure, diuretics, malignancy)!
Triggering factors of a gouty attack
Hyperuricaemia # gout
Gouty arthritis = 1) precipitation of monosodium-
urate crystals + 2)inflammation
Precipitation:
Urate concentration - excessive eating, fasting,
dehydration, infection, chemotherapy
pH ↓- alcohol, lactate acidosis, ketoacidosis
temperature ↓- typical onset of symptoms at night and
presentation at acral body parts (toe, finger, elbow,
ear)
Acute gouty arthritic attack
Very acute onset
Very painful swelling, redness, tenderness
I. MTP joint > ankle, knee> other foot joints >
upper extremity
Fever, subfebrility may be present
Spontaneous resolution within 5-8 days
Acute gouty arthritis
Acute gouty arthritis
Chronic gout
The attacks tend to occur more frequently,
resolve more slowly, and involve more and more
joints
Chronic joint damage develops (chronic pain,
loss of range of motion, contracture,
radiographic bone destruction
Tophus formation (monosodium-urate crystal
containing nodules around the joints (juxta-
articular) or in soft tissues (subcutaneous, ear,
occasionally in viscers)
Gout – tophi, deforming arthritis
Tophaceous gout
Chronic olecranon bursitis in gout
Chronic olecranon bursitis in gout
Subcutaneous tophi
Chronic tophaceous gout
Tophi on the ear
Chronic tophus with subcutaneous
fistula formation
The kidney in gout
1. Sodium-urate urinary stones
2. Acute urate nephropathy (during excessive cell destruction e.g. chemotherapy) – acute renal failure, acute tubular obstruction and necrosis
3. Chronic urate nephropathy: signs of chronic tubulo-interstitial damage
Frequent differential-diagnostic question: Chronic renal insufficiency → secondary
hyperuricaemia?
or Chronic hyperuricaemia → chronic urate
nephropathy?
Diagnosis of gout
Absolute proof: the demonstration of urate crystals in the synovial fluid
Probable diagnosis:
typical clinical picture
Hyperuricaemia – but: serum urate levels are often normal during gouty attack
Chronic tophaceous gout
typical radiographic pictures
rarely a differential diagnosis from rheumatoid arthritis or spondylarthropathies may be challenging
Intracellular urate crystals
Light microscopy Polarisation microscopy
Intra-articular urate crystals –
polarisation microscopic image
Radiographic hallmarks of advanced,
tophaceous gout
.
The simultaneous
occurrence of erosions (1),
enlargement of
the width of joints (2),
overhanging edges (3a,
3b), and sclerotic,
degenerative changes in
the wrist.
Gout – radiographic changes in the feet
Punched out
erosions + soft
tissue
calcification
Arrow: soft tissue
calcification
The treatment of gout
Treatment of acute attacks
Prevention of subsequent attacks and
chronic bone and joint destruction
The evaluation and treatment of associated
diseases (METABOLIC SYNDROME)
Dietary treatment of gout High purin content
Best to avoid: Anchovies, sardines, herring, mussels, codfish, scallops, trout, haddock,
veal, venison, turkey, high fructose-content juices and sodas and alcoholic beverages
Moderate purin content
May eat occasionally: Asparagus, beef, bouillon, chicken, crab, duck, ham, kidney beans,
lentils, lima beans, mushrooms, lobster, oysters, pork, shrimp, spinach
Low purin content
No limitation: Coffee, fruits, breads, grains, macaroni, cheese, eggs, milk products,
sugar, tomatoes and green vegetables (including lettuce and excluding vegetables listed above
MODERATE CALORY INTAKE (IF OBESITY), APPROPRIATE SUGAR (IF DIABETES) OR CHOLESTEROL (IF HYPERCHOLESTEROLAEMIA, ATHEROSCLEROSIS)!!!
Chronic maintainance drug therapy of
gout (hypouricaemic therapy)
Allopurinol Xanthin-oxidase inhibitor
Decreases hepatic uric acid production (xantin and hypoxantin are more soluble)
Dose: 100 mg/day → 600 mg/day
Reduced doses in renal and hepatic insufficiency!
Occasionally severe allergic reactions (erythroderma, toxic epidermal necrolysis, „allopurinol hypersensitivity syndrome”: fever, generalised rash, systemic vasculitis, hepatic and renal failure, eosinophilia)
Febuxostate More effective, better pharmacokinetics, less side
effects
Indicated in cases of allopurinol-allergy
Further drugs to treat
hyperuricaemia/gout
Uricosuric agents Sulfinpyrazone
Less effective
Urate stones – for prevention, urine alkalinisation is important!
Uricase Rasburicase (recombinant uricase enzyme)
Interleukine-1 antagonist biological therapies Canakinumab, rilonacept
Indications for urate lowering treatment: repeated gouty attacks, tophaceous gout, repeated urinary stone formation, urate nephropathy, prophylaxis during chemotherapy (→ hyperuricaemia without the above symptoms: no treatment is indicated)