Hyperureacmia and gout

Urates
 Is the final breakdown product of purine degradation in
humans
 The ionized forms of uric acid, predominante in plasma,
extracellular fluid and synovial fluid.
 Approximately 98% existing as monosodium urate at pH
7.4

 Plasma is saturated with monosodium urate at a concentration
of 6.8 mg/dl.
 At higer concentrations, plasma is therfore supersaturated,
creating the potential for urate crystal precipitation.
 Urate production varies with the purine content of the diet and
the rates of purine biosyntesis, degradation and salvage.
 2/3 to ¾ of urate is excreted by kidneys, and most of the
remainer is eliminated through the intestines.

Renal handling
 Glomerular filtration
 Tubular reabsorption
 Secretion
 Postsecretory reabsorption
 Serum urate levels vary with age and sex.
 Children: 3 to 4 mg/dl
 Adult men: 6 to 6.8 mg/dl

 Uric acid is more soluble in urine than in water.
 The pH of urine greatly influences its solubility.
 pH 5 urine is saturated with uric acid at concentrations ranging
from 6 to 15 mg/dl.
 At pH 7 saturation is reached at concentration between 158
and 200mg/dl
 Defined as a plasma urate concentration > 7.0 mg/dl = ?

Hyperuricemia
 Can result from:
 Increased production of uric acid
 Decreased excretion of uric acid
 Combination of the two processes.

Increased Urate Production
 Diet provides an exogenous source of purines and,
accordingly, contributes to the serum urate in proportion to its
purine content.
 Foods high in nucleic acid: liver, thymus and pancreas,
kidney.
 Restriction intake: reduces: 1 mg/dl
 Endogenous sources:
 De novo purine biosynthesis: 11 step

Decreased Uric Acid Excretion
 Alterated uric acid excretion could result from decreased
glomerular filtration, decreased tubular secretion or
enhanced tubular reabsorption.
 Decreased tubular secretion of urate causes the secondary
hyperuricemia of acidosis.
 Diabetic ketoacidosis, starvation, ethanol intoxication, lactic
acidosis, and salicylate intoxication are accompanied by
accumulations of organic acids (B-hydroxybutyrate,
acetoacetate, lactate or salicylates) that compete with urate
for tubular secretion.

Combined Mechanisms
 Alcohol intake promotes hyperuricemia:
 Fast hepatic breakdown of ATP and increases urate
production.
 Can induce hyperlacticacidemia, and inhibition of uric acid
secretion.
 The higher purine content in some alcoholic beverages such as beer
may also be a factor.

Complications of Hyperuricemia
 The most recognized complication of hyperuricemia is gouty
arthritis
 Nephrolithiasis
 Urate Nephropathy
 Uric Acid Nephropathy
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Nephrolithiasis
 The prevalence of nephrolithiasis correlates with the serum
and urinary uric acid levels. (Serum urate levels 13 mg/dl &
Urinary uric acid excretion > 1100 mg/d)
Urate Nephropathy
 Deposits of monosodium urate crystals surrounded by a giant cell
inflammatory reaction in the medullary intrerstitium
Uric acid nephropathy
 Precipitation in renal tubules and collecting ducts cause
obstruction to urine flow.

An acute attack of gout has a rapid onset, with pain being
maximal at 6–24 h of onset.
The first attack affects a single joint in the lower limbs in 85–
90% of cases (the first metatarsophalangeal joint (big toe).
The next affected are the mid-tarsi, ankles, knees and arms.
The affected joint is hot, red and swollen with shiny overlying
skin.
Presentation and diagnosis

Crystal-induced arthritides
 MSU (monosodium urate)
 CPPD (calcium pyrophosphate dihydrate)
 HA (calcium hydroxyapatite)
 Calcium oxalate (CaOx)

Monosodiumurate Gout
 Affecting middle-aged to elderly men.
 Women represent only 5 to 17% of all patients.

Monosodiumurate Gout
 Associated with an
 Increased uric acid,
 Hyperuricemia,
 Episodic acute and chronic arthritis,
 Deposition of MSU crystals in connective tissue tophi and
kidneys.

Acute and chronic arthritis
 Acute arthritis is the most frequent early clinical manifestation
of MSU gout.
 Usually only one joint is affected initially
 Polyarticular acute gout is also seen in male hypertensive
patients with ethanol abuse as well as in postmenopausal
women.

 The patient may also have a fever, leucocytosis, raised
erythrocyte sedimentation rate (ESR).
 The attack may also be preceded by prodromal
symptoms such as anorexia, nausea orchange in mood.
 Following resolution of the attack, there may be pruritis
and desquamation of the overlying skin on the affected
joint.

 Several events may precipitate acute gouty arthritis:
 Dietary excess
 Genetics (SLC22A1 2, SLC2 A9 )
 Comorbidities (obesity, dyslipidemia, glucose intolerance and
hypertension)
 Renal disease (urate crystals in the interstitium and tubules of the
kidney.)
 Trauma
 Surgery
 Excessive alcohol ingestion
 Medication (Glucocorticoid withdrawal)
Risk factors

Laboratory Diagnosis
 Even the clinical appearance strongly suggests gout. The
diagnosis should be confirmed by needle aspiration of acute or
chronically inflamed joints or tophaceous deposits.
 Acute septic arthritis several of the other crystalline –
associated arthropathies, and psoriatic arthritis may present
with similar clinical features.
 Effusion appear cloudy due to leukocytes and a large amounts
crystals ocassionally produce a thick pasty or chalky joint fluid.

Radiographic Features
 Cystic changes, well-defined erosions described as punched-
out lytic lesion.
 Soft tissue calcified masses (chronic tophaceous gout)

Monosodium urate crystals form in cartilage and fibrous tissues
(protected)
Crystals are shed into the joint space or bursa that inflammatory
reaction occurs
The shedding of crystals can be triggered by a number of factors
including direct trauma, dehydration, acidosis or rapid weight loss.
Pathogenesis

 There is increased urinary urate excretion with a lowering of
serum uric acid which leads to partial dissolution of
monosodium urate crystals and subsequent shedding of
crystals into the joint space.
 The shed crystals are phagocytosed by monocytes and
macrophages, activating protein-3 (NALP3) inflammasome
and triggering the release of interleukin-1(IL-1) and other
cytokines, a subsequent infiltration of neutrophils and the
symptoms of an acute attack

Course of disease
 The course of gout follows a number of stages
 Initially, the patient may be asymptomatic with a raised serum
uric acid level often a second attack occurs within 6–12
months.
 Affect more than one joint and may spread to the upper limbs.
 Untreated disease can result in chronic tophaceous gout, with
persistent low-grade inflammation in a number of joints
resulting in joint damage and deformity.

 Tophi deposition can occur anywhere in the body, but they are
commonly seen on the helix of the ear, within and around the
toe or finger joints, on the elbow, around the knees or on the
Achilles tendons.
 The skin overlying the tophi may ulcerate and extrude white,
chalky material composed of monosodium urate crystals.

Treatment aims in gout
 Rapid alleviation of the acute attack
 Prevention of future attacks
 Lower serum uric acid levels to below saturation point
 Reduce risk of co-morbidities, for example, cardiovascular
disease
 Lifestyle modification

Treatment
 The management of gout can be split into
 The rapid resolution of the initial acute attack
 Long-term measures to prevent future episodes.
 Gout is often associated with othermedical problems including
obesity, hypertension, excessive alcohol and the metabolic syndrome
of insulin resistance, hyperinsulinaemia, impaired glucose intolerance
and hypertriglyceridaemia.

 This contributes to the increased cardiovascular risk and
deterioration of renal function seen in patients with gout.
 Management is not only directed at alleviating acute attacks and
preventing future attacks, but also identifying and treating other
co-morbid conditions such as hypertension and hyperlipidaemia.
 Pharmacological measures should be combined with non-
pharmacological measures such as weightloss, changes in diet,
increased exercise and reduced alcohol consumption.

Management of acute attackof gout
 Management of an acute attack of gout Promptly and safely resolve
pain
 First line: NSAID (use maximum dose)
 Second line: Colchicine
 Third line: Corticosteroid (consider first line in mono-articular disease)
 (±Simple and opiate analgesia if needed, for example, paracetamol,
codeine dihydrocodeine)
 Rest the joint 1–2 days and treat with ice
 Remove contributing factors
 Review medication
 Review lifestyle

Management of chronic gout
 The presence of hyperuricaemia is not an indication to commence
prophylactic therapy.
 Some patients may only experience a single episode and a change in
lifestyle, diet or concurrent medication may be sufficient to prevent
further attacks.
 Patients who suffer one or more acute attacks within 12 months of the
first attack should normally be prescribed prophylactic urate-lowering
therapy.

The aim of prophylactic gout treatment
 The aim of prophylactic gout treatment is to maintain the serum
urate level below the saturation point of monosodium urate
(300 μmol/L).
 If the serum urate is maintained below this level, crystal
deposits dissolve and gout is controlled.
 Prophylactic treatment should not be initiated until an acute
attack of gout has completely resolved,
 Usually 2 to 3 weeks after symptom resolution. Once started,
prophylactic treatment should be continued indefinitely even if
further acute attacks develop.

Criteria for starting prophylactic therapy for
gout
 One ormore acute attacks within 12 months of the first attack
 Tophi present at the first presentation of an acute attack
 Presence of uric acid stones
 Need to continue medication associated with raised uric acid
levels, for example diuretics
 Young patients with a family history of renal or cardiac disease

Classification of prophylactic agents used to
lower serum urate
 Drugs that lower serum uric acid can be classified into three
groups according to their pharmacological mode of action
Uricostatic agents: Allopurinol,
Febuxostat
Uricosuric agents: Benzbromarone,
Probenecid,
Sulphinpyrazone
Uricolytic agents: Rasburicase,
Polyethylene glycol-uricase
Inhibit the xanthine
oxidase enzyme
Increase excretion
of uric acid
Uric acid to allantoin
(urate oxidase)

Hyperureacmia and gout

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