GOUTDr. Mohanad

Purines

Purines are natural substances found in all of the body's cells, and in virtually all foods.

The reason for their widespread occurrence is simple: purines provide part of the chemical structure of our genes and the genes of plants and animals

When cells die and get recycled, the purines in their genetic material also get broken down.

Uric acid is the chemical formed when purines have been broken down completely.

Hyperuricemia The condition when there are high

concentrations of uric acid in the blood.

Serum levels of uric acid are >7mg/dL (Normally, 2.4-6mg/dL in females; 3.4-7mg/dL in males)

At such a high level, uric acid tends to aggregate and form crystals

Primary Hyperuricemia: an innate defect in purine metabolism and/or uric acid excretion

Secondary Hyperuricemia: high uric acid levels due to medications/medical conditions such as diabetic ketoacidosis, psoriasis, chronic lead poisoning

Most uric acid dissolves in blood and travels to the kidneys, where it passes out in urine.

If your body produces too much uric acid or doesn't remove enough if it, you can get sick.

High levels of uric acid in the body is called Hyperuricemia.

Purine nucleotides

hypoxanthine

xanthine

Uric acid

Xanthine oxidase

Alimentary excretion

Urinary excretion

Tissue deposition in excess

Urate crystal microtophi

Phagocytosis with acute inflammation and arthritis

uricosurics

colchicine NSAID

Allopurinol

Oxypurinol

Uric Acid

Uric acid is the end product in purine metabolism

Excretion of uric acid removes nitrogenous wastes from body

2/3 of uric acid made is excreted via kidneys; 1/3 via GI tract

Urate: protonated form of uric acid

Uric acid can accumulate due to: Overproduction of purine nucleotides Enhanced cell turnover (purine degradation) Decreased in purine salvage pathway Underexcretion of uric acid

Predisposition to many diseases

People may live with elevated uric acid levels without experiencing any symptoms

GOUT

Gout and gouty arthritis

Transient attacks of acute arthritis initiated by crystallization of urates and neutrophils, followed by chronic gouty arthritis with tophi in joints and urate nephropathy

Sites: 50% have initial attack in first metatarsophalangeal joint; also ankles, heels, knees, wrists, fingers, elbows

Gout

Affects less than 0.5% of the population.

It is a common condition, presenting in 1-4% of adult men.

Due to familial disposition, incidence may be as high as 80% in families affected by disorder.

Alcohol and Gout

alcohol metabolism contributes to urate retentionsome red wines contain purines or oxypurines,

which lead to an increased purine loadalcohol may contribute to obesity which is

associated with under excretion of uric acid

Patients with a history of gout are advised to drink plenty of fluid, approximately 2 litres per day (nonalcoholic).

GOUT

Primary gout (90%): idiopathic with overproduction of uric acid

Hyperuricemia in the absence of other diseaseAsymptomatic hyperuricemia can precede gout

Impaired secretion by kidneys

Secondary gout (10%): increased nucleic acid turnover due to

chronic renal disease, HGPRT deficiency( hypoxanthine-guanine

phosphoribosyl transferase deficiency)Tumors

LeukemiasLymphomasAfter chemotherapy

AlcoholismAccelerated ATP catabolism

"se co n da ry go u t"

H G P R T

E n zym a tic d e fic ie n cy

"se co n da ry go u t"

L e u ke m ia

In c rea se d n uc le ic a c id tu rno ver

"p rim a ry g o u t"

U n kn o w n d e fe ctca u sin g d e cre a se d exc re tion

H yp e ru rice m ia

GOUT

Arthritis: synovial fluid is poorer solvent for sodium urate than plasma, so with hyperuricemia.

Urates in joint fluid crystallize, particularly in ankle due to lower temperature; crystals develop in synovial lining cells, stimulate formation of antibodies, which accelerates formation of new crystals.

Release of crystals attracts neutrophils and complement, (generates c3a, c5a, attracts more neutrophils),

Releases free radicals, releases lysosomal enzymes

GOUT

This will eventually causes acute arthritis that last days to weeks without treatment; repeated attacks of acute arthritis cause

Renal failure, urate stones

Risk factors for gout with Hyperuricemia are:

Age > 30 years, Male, familial history of gout, Alcohol use, Obesity, Thiazide administration(reduce the clearance of uric

acid)

Pathogenesis

Enzymatic deficiencies and increased nucleic acid turnover account for only 10% of gout patients.

Remaining 90% are “primary gout” due to an unknown defect limiting the ability to excrete uric acid.

Pathogenesis

Uric acid normally dissolves in plasmaPoorly soluble in synovial fluid and

precipitates out as MSU crystals (monosodium urate  crystals )

Pathogenesis

Hyperuricaemia

May be asymptomatic

Deposition of monosodium urate crystals in synovial tissue(contain various Ig’s, complement, fibrinogen, fibronectin)

Complement activated

Neutrophils phagocytose & lyse crystals

Release chemical mediators (e.g. TNF-α; IL-1)

ACUTE GOUTY ARTHRITIS

May resolve & become asymptomatic

(INTERCRITICAL GOUT)

May have recurrent episodes

Large deposits of chalky white urate tophi

Chronic granulomatous inflammatory condition

Fibrosis of synovium

Erosion of articular cartilage

CHRONIC TOPHACEOUS ARTHRITIS

ankylosis

Tophi may be deposited in soft tissue

Can ulcerate if sub-cutaneous

Pathogenesis of Renal Involvement

Hyperuricaemia

Freely filtered by glomerulus, but reabsorbed in proximal convulated tubules

Precipitation in renal tubules

Tubule obstruction

Crystal formation in interstitium

Renal stones

Recurrent pyelonephritis

Crystal Studies

Sodium urate crystals viewed under polarized light with a red plate makes those in the plane of the long axis of the red plate yellow, which indicates that they are negatively birefringent.

                                          

Clinical features

Acute gouty arthritisPainfulInvolves one joint initially, then polyarticularPodagra (painful, red metatarsophalangeal

joint)Tophaceous gout

Development of tophiChalky, cheesy, yellow-white, pasty deposits of

monosodium urate crystalsHelix and antihelix of earAchilles tendon

Stages of Gout

Asymptomatic HyperuricemiaAcute AttackIntercritical PeriodChronic Gout

Acute gout

Sudden onset Lasts 1-2wMay be triggered by – trauma, operation, alcohol,

exercise

Sites 1st MTP (75%)Ankle Finger Olecranon

Chronic gout

Polyarticular gout Tophi may form around joints and often also in the

pinna of the ear and with time may ulcerate and discharge

May cause joint stiffness and deformity as a result of joint erosion

May cause renal damage due to deposition of urate crystals in the renal parenchyma

Urate urolithiasis occurs in 10%; rarely chronic urate nephropathy with renal failure may develop

Acute on chronic gout

Diagnosis

More than one attackMaximum inflammation

in one dayMonoarthritisRednessFirst MTP involvedUnilateral first MTPUnilateral tarsal attack

TophusHyperuricemiaAsymmetric swellingMSU crystals in joint

fluidJoint fluid culture

negative

Diagnosis

Based on history and physical examinationConfirmed by arthrocentesis

Urate crystals: needle-shaped negatively birefringent either free floating or within neutrophils & macrophages.

Uric acid level non specific.30% may show normal level

Urine collection:

GOUT

Gross: chalky white appearance of gouty depositsMicro: early - edematous synovium with acute and

chronic inflammatory infiltrate Late - tophi (large aggregates of urate crystals,

granulomatous inflammation, hyperplastic fibrotic synovium);

Gout crystals are long, slender, needle shaped, but difficult to visualize with routine staining because they are dissolved during formalin processing (crystals are water soluble); easier to identify on scrape or with alcohol fixation

GOUT

With chronic disease, urate deposits may be present in soft tissue, ligaments, skin

Gouty deposits may be surrounded by fibrous tissue and be rimmed by histiocytes and giant cells

Gout from sodium urate crystals Gout from sodium urate crystals deposited in joints. deposited in joints.

This is gout. Gouty arthritis results from deposition of sodium urate crystals in joints.

The joint most often affected is the first MP joint (big toe) as seen here.

Acute attacks are characterized by severe pain, swelling, and erythema of the joint.

Gout or pseudogout?

Gout >40 small joints esp 1st

MTP Severe joint pain

swelling

Uric acid crystals neg bifringent

Rest, nsiad prohylaxishyperuricaemia

Pseudogout Elderly Large joints esp knee

Mod pain and swelling

Calcium pyrophosphate positively bifringent

Rest, nsaid, joint aspiration

TreatmentLife style (food)

ColchicineProphylactic

Probenecid & sulfinpyrazoneInterfere with urate resorption

AllopurinolInhibitor of enzyme that converts the xanthine and

hypoxanthine to uric acid