Dr. Mohd Viquasuddin SaimDNB General Medicine resident Medwin hospital

Purines (adenine and guanine) and pyrimidines (cytosine, thymine, uracil) serve fundamental roles in

in the replication of genetic material, gene transcription, protein synthesis, cellular metabolism

hyperuricemia and gout there is increased production or impaired

excretion of a metabolic end product of purine metabolism (uric acid)

Understanding the biochemical pathways has led to the development of specific forms of treatment, such as the use of allopurinol, to reduce uric acid production.

Uric acid is the final breakdown product of purine degradation in humans.

It is a weak acid with pKas of 5.75 and 10.3. Urates, the ionized forms of uric acid,

predominate in plasma extracellular fluid and synovial fluid, with 98% existing as monosodium urate at pH 7.4.

Plasma is saturated with monosodium urateat a concentration of 405 mol/L (6.8 mg/dL) at 37°C.

At higher concentrations, plasma is therefore supersaturated, creating the potential for urate crystal precipitation.

plasma urate concentrations can reach 4800 mol/L (80 mg/dL) without precipitation, perhaps because of the presence of solubilizing substances.

The pH of urine greatly influences the solubility of uric acid.

At pH 5.0, urine is saturated with uric acid at concentrations ranging from 360 to 900 mol/L (6–15 mg/dL).

At pH 7, saturation is reached at concentrations between 9480 and 12,000 mol/L (158 and 200 mg/dL).

Ionized forms of uric acid in urine include mono-and disodium, potassium, ammonium, and calcium urates

purine nucleotides are synthesized and degraded in all tissues

urate is produced only in tissues that contain xanthine oxidase, primarily the liver and small intestine

Urate production varies with the purine content of the diet and the rates of purine biosynthesis, degradation, and salvage

Normally, two-thirds to three-fourths of urate is excreted by the kidneys, and most of the remainder is eliminated through the intestines.

The kidneys clear urate from the plasma and maintain physiologic balance by utilizing specific organic anion transporters (OATs), including urate transporter 1 (URAT1) and human uric acid transporter (hUAT)

URAT1 and other OATs carry urate into the tubular cells from the apical side of the lumen

Once inside the cell, urate must pass to the basolateral side of the lumen in a process controlled by the voltage-dependent carrier hUAT.

the renal handling of urate/uric acid: (1) glomerular filtration, (2) tubular reabsorption, (3) secretion (4) postsecretory reabsorption these processes have been considered

sequential, it is now apparent that they are carried out in parallel

. URAT1 is a novel transporter expressed at the apical brush border of the proximal nephron

Uricosuric compounds directly inhibit URAT1 on the apical side of the tubular cell (so-called cis-inhibition)

In contrast, antiuricosuric compounds (those that promote hyperuricemia), such as nicotinate, pyrazinoate, lactate, and other aromatic organic acids, serve as the exchange anion inside the cell, thereby stimulating anion exchange and uratereabsorption (trans-stimulation).

The activities of URAT1, other OATs, and sodium anion transporter result in 8–12% of the filtered uratebeing excreted as uric acid.

ACTH Ascorbic acid Calcitonin Estrogens Glucocorticoids Losartan Probenicid Radiocontrast agents Salicylates >2gm/day

Most children have serum urate concentrations 3–4 mg/dL

Levels begin to rise in males during puberty but remain low in females until menopause

Mean serum urate values of adult men and premenopausal women are (6.8 and 6 mg/dL), respectively

After menopause, values for women increase to approximate those of men

In adulthood, concentrations rise steadily over time and vary with height, body weight, blood pressure, renal function, and alcohol intake.

Hyperuricemia can result from increased production or decreased excretion of uric acid or from a combination of the two processes

Sustained hyperuricemia predisposes some individuals to develop clinical manifestations including :

gouty arthritis, urolithiasis, renal dysfunction

Hyperuricemia is defined as a serum urateconcentration 6.8 mg/dL.

The risk of developing gouty arthritis or urolithiasis increases with higher urate levels and escalates in proportion to the degree of elevation.

Hyperuricemia is present in between 2 and 13.2% of ambulatory adults

more frequent in hospitalized individuals.

Urate over producers Under excretors Combination of both

Primary idiopathic HPRT deficiency, PRPP synthetase overactivity Hemolytic processes Lymphoproliferative diseases,

Myeloproliferative diseases Polycythemia vera Psoriasis, Paget's disease Glycogenosis III, V, and VII Rhabdomyolysis Exercise Alcohol, Obesity Purine-rich diet

Primary idiopathic Renal insufficiency, Polycystic kidney disease, Diabetes

insipidus, Hypertension Acidosis : Lactic acidosis, Diabetic ketoacidosis, Starvation

ketosis Berylliosis, Sarcoidosis, Lead intoxication Hyperparathyroidism, Hypothyroidism Toxemia of pregnancy Bartter's syndrome Down syndrome Drug ingestion : Salicylates (>2 g/d), Diuretics, Alcohol,

Levodopa, Ethambutol, Pyrazinamide, Nicotinic acid, Cyclosporine

Glucose-6-phosphatase deficiency Fructose-1-phosphate aldolase deficiency Alcohol Shock

Diet contributes to the serum urate in proportion to its purine content.

Strict restriction of purine intake reduces the mean serum urate level by about 1 mg/dL and urinary uric acid excretion by 200 mg/dL

Foods high in nucleic acid content include liver, "sweetbreads" (i.e., thymus and pancreas), kidney, and anchovy.

Endogenous sources of purine production also influence the serum urate level.

De novo purine biosynthesis is an 11-step process that forms inosine monophosphate (IMP)

The rates of purine biosynthesis and urate production are determined, for the most part, by amidophosphoribosyltransferase (amidoPRT), which combines phosphoribosylpyrophosphate (PRPP) and glutamine.

A secondary regulatory pathway is the salvage of purine bases by hypoxanthine phosphoribosyltransferase (HPRT).

HPRT catalyzes the combination of the purine bases hypoxanthine and guanine with PRPP to form the respective ribonucleotides IMP and guanosine monophosphate (GMP).

Serum urate levels are closely coupled to the rates of de novo purine biosynthesis, which is driven in part by the level of PRPP

Both increased PRPP synthetase activity and HPRT deficiency are associated with overproduction of purines, hyperuricemia, and hyperuricaciduria

Accelerated purine nucleotide degradation can also cause hyperuricemia

Hyperuricemia can result from excessive degradation of skeletal muscle ATP after strenuous physical exercise or status epilepticusand in glycogen storage diseases types III, V, and VII

The hyperuricemia of myocardial infarction, smoke inhalation, and acute respiratory failure may also be related to accelerated breakdown of ATP

More than 90% of individuals with sustained hyperuricemia have a defect in the renal handling of uric acid.

Gouty individuals excrete 40% less uric acid than nongouty individuals for any given plasma urateconcentration.

Uric acid excretion increases in gouty and nongouty individuals when plasma urate levels are raised by purine ingestion or infusion, but in those with gout, plasma urate concentrations must be 1–2 mg/dL higher than normal to achieve equivalent uric acid excretion rates.

Altered uric acid excretion results from decreased glomerular filtration, decreased tubular secretion, or enhanced tubular reabsorption.

Decreased urate filtration does not appear to cause primary hyperuricemia but does contribute to the hyperuricemia of renal insufficiency.

hyperuricemia is invariably present in chronic renal disease Uric acid excretion per unit of glomerular filtration rate

increases progressively with chronic renal insufficiency, but tubular secretory capacity tends to be preserved, tubular reabsorptive capacity is reduced, and extrarenalclearance of uric acid increases as renal damage becomes more severe.

Many agents that cause hyperuricemia exert their effects by stimulating reabsorption rather than inhibiting secretion.

This appears to occur through a process of "priming" renal urate reabsorption through the sodium-dependent loading of proximal tubular epithelial cells with anions capable of trans-stimulating uratereabsorption

carboxylates are well known to cause hyperuricemia, including pyrazinoate (from pyrazinamide treatment), nicotinate (from niacin therapy), and the organic acids lactate,beta -hydroxybutyrate, and acetoacetate

Alcohol promotes hyperuricemia because of increased urate production and decreased uric acid excretion.

Excessive alcohol consumption accelerates hepatic breakdown of ATP to increase urateproduction.

Alcohol consumption can also induce hyperlacticacidemia, which blocks uric acid secretion.

The higher purine content in some alcoholic beverages such as beer may also be a factor.

Hyperuricemia does not necessarily represent a disease, nor is it a specific indication for therapy. The decision to treat depends on the cause and the potential

consequences of the hyperuricemia in each individual. Quantification of uric acid excretion can be used to determine

whether hyperuricemia is caused by overproduction or decreased excretion.

On a purine-free diet, men with normal renal function excrete <3.6 mmol/d (600 mg/d).

Thus, the hyperuricemia of individuals who excrete uric acid above this level while on a purine-free diet is due to purineoverproduction; for those who excrete lower amounts on the purine-free diet, it is due to decreased excretion.

gouty arthritis Nephrolithiasis urate nephropathy :a rare cause of renal

insufficiency attributed to monosodium uratecrystal deposition in the renal interstitium

uric acid nephropathy : a reversible cause of acute renal failure resulting from deposition of large amounts of uric acid crystals in the renal collecting ducts, pelvis, and ureters.

Physiological : pregnancy Pathological : SIADH, Fanconi’s syndrome

One of the earliest diseases to be recognized in humans

first described in ancient Egypt in 2640 B.C known as "the disease of kings fifth century B.C.,Hippocrates described gout

as unwalkable disease sixth century A.D. colchicine recognised as

gout remedy

is the most common inflammatory arthritis affecting men

most often presents as recurrent, self-limiting episodes of severe acute arthritis

central feature of gout is deposition of MSU crystals

The gold standard for diagnosis of gout is identification of MSU crystals within tissue or synovial fluid

male sex, increasing age, socio-economic deprivation,

Polynesian ethnicity obesity, chronic renal impairment, renal

transplantation cardiovascular disease, type 2 diabetes, hypertension, heart failure,

hypertriglyceridaemia, and psoriasis Diuretic and cyclosporine usage

high intake of beer and spirits, sugar-sweetened soft drinks, fructose, meat, and seafood

Weight gain and obesity in younger life are strongly associated with development of gout

low-fat dairy products, coffee, and vitamin C are associated with reduced risk

first attack of gout most often presents as rapid onset of acute inflammation affecting the first metatarsophalangeal (MTP) joint or other joint in the lower limb

Patients describe severe joint pain with difficulty walking and performing daily activities

Examination of the affected joint shows the cardinal features of inflammation; erythema, heat, tenderness, swelling, and loss of joint mobility

severe gout attack, patients may also be systemically unwell with fever.

The acute gout attack typically resolves spontaneously after 7–10 days

In the presence of persistent hyperuricaemia, recurrent flares occur, with increasingly frequent and prolonged attacks which may affect numerous joints including those in the upper limbs

Problems of tophaceous gout cosmetic problems, ulceration and superimposed infection, mechanical obstruction of joint movement, Bone and cartilage damage musculoskeletal disability

heavy alcohol intake, dehydration, joint trauma, medical illness, surgery, intake of high-purine diet Urate lower therapy

Chronic gout has an important impact on health-related quality of life and musculoskeletal function.

In particular, recurrent gout flares, the presence of joint inflammation and tophi are associated with disability and poor health-related quality of life.

Work productivity is also reduced in patients of working age with severe gout, with an estimated mean work day loss of 25.1 days per year

thiazide diuretic use in patients with hypertension may increase serum urateconcentrations

chronic kidney disease may limit the use of non-steroidal anti-inflammatory drugs (NSAIDs) and/or colchicine for management of acute flares

blood sugar control may be difficult in patients with coexistent diabetes receiving corticosteroids

confirmed by identification of MSU crystals in synovial fluid or tophus

synovial fluid analysis typically shows an inflammatory picture with high concentrations of neutrophils

Blood testing typically shows signs of acute infl ammation with neutrophil leucocytosisand high acute phase reactants

Low complement levels common

during an acute gout flare, serum urateconcentration drops into the normal range in approximately 40% of patients

repeat measurement of the serum urateconcentration in the convalescent period is required

plain radiographs are normal in patients with recent presentation of gout

In patients with established disease, typical plain radiographic features are asymmetric soft -tissue masses (tophi) and well-corticated bone erosions with overhanging edge

Dual energy CT (DECT) for non-invasive diagnosis of gout

Three therapeutic goals 1. treatment of acute gout flares 2.prophylaxis against acute gout flares

(usually at the time of initiating ULT) 3. long-term preventive treatment of chronic

gout with ULT

goal of treating acute gout is resolution of pain and inflammation

Treatment should be commenced as soon as possible after development of symptoms

includes rest, icing of the affected joint, and Analgesia

NSAIDs are first-line treatment in patients without contraindications.

These drugs are most effective when used in a fast-acting preparation and at full dose

naproxen 500 mg twice daily, indomethacin50 mg three times daily

give major clinical response within 2 days COX-2 inhibitors such as etoricoxib (120 mg

daily) and lumiracoxib (400 mg daily) have similar efficacy in treating acute gout

COX-2 inhibitors better tolerated

has been used for centuries for treatment of acute gout

a low dose of colchicine (1.8 mg total over 1 hour) was as effective as a high dose (4.8 mg total over 6 hours)

clinical response in 38% of patients within 24 hours

FDA recommends that colchicine dosing for acute gout should be 1.2 mg stat followed by 0.6 mg in 1 hour

may cause severe drug interactions with CYP3A4 inhibitors

(ciclosporin, clarithromycin, ketoconazole, verapamil, diltiazem, erythromycin)

dose of colchicine should also be reduced in patients with renal or liver disease

Loperamide best antidote for colchicineinduced diarrhea

Intra-articular corticosteroid injection of the affected joint leads to rapid improvement in pain and inflammation

Oral prednisolone is useful in patients where the use of NSAIDs and colchicine is harmful

Adrenocorticotropic hormone (ACTH) injection is also effective, typical doses are 40 IU

M.O.A : adrenal corticosteroid release and also activation of the melanocortin type 3 receptor

use of anti-inflammatory agents to prevent flares in patients with intercurrent or chronic gout

relevant when commencing urate lowering therapy

Low-dose colchicine (0.5–1.5 mg daily) is the most frequently used prophylactic treatment for gout

Regular use of NSAIDs to be avoided due to renal impairment and hypertension in gout

Recommended for : Recurrent gout flares (more than one fl are

per year), gouty tophi, Chronic gouty arthropathy radiographic erosions serum urate concentration (6 mg/dL) is

recommended

three main groups 1. the xanthine oxidase inhibitors, 2. uricosuric agents 3. recombinant uricase Vitamin C at 500mg-1000 mg daily has a

modest urate-lowering eff ect

Xanthine oxidase is a critical enzyme in the metabolism of purines to urate,

catalyses the conversion of hypoxanthine to xanthine and xanthine to urate

Allopurinol and febuxostat are two agents currently used

allopurinol hypersensitivity syndrome can cause progressive renal failure

Dose reduction needed when patient on azathioprine

Approved by the FDA in 2009 upto dose of 80mg daily

febuxostat has superior urate-lowering efficacy compared allopurinol

well tolerated does not require dose adjustment in patients

with mild–moderate renal or hepatic impairment

these drugs have the potential to promote urate stone formation

should be avoided in patients with nephrolithiasis

Liberal fl uid intake is recommended urine alkalinization should be considered by

using sodium bicarbonate (3–7.5 g daily) or potassium citrate (7.5g daily)

Probenicid, Sulphinpyrazone, Benzbromarone are the drugs

Uricase (urate oxidase) converts urate to 5-hydroxy isourate and H 2 O 2 , with subsequent formation of allantoin

Allantoin is soluble and is readily eliminated by the kidney

humans lack a functional uricase gene profound reductions in serum urate

concentrations often to undetectable levels Eg. Rasburicase, Pegloticase

ReferrencesHarrison’s 18TH editionOxford’s rheumatology