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

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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 or change 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 (SLC22A12, SLC2A9) 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 other medical 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 attack of 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 or more 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, SulphinpyrazoneUricolytic 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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