Dr. Gangadhar ChatterjeeMBBS;MD

Assistant ProfessorRCSM Govt. Medical college, Kolhapur, MH, India

• 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 theremainder is elimínated 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

• Defined as a plasma urate concentration > 7.0 mg/dl

• 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

and anchovy.

• Restriction intake: reduces: 1 mg/dl

• Endogenous sources:

• De novo purine biosynthesis: 11 step

• Increased PRPP synthetase activity and HPRT deficiency are

associated with overproduction of purine, hyperuricemia and

hyperuricaciduria.

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 urateproduction.

• Can induce hyperlacticacidemia, and inhibition of uricacid secretion.

• The higher purine content in some alcoholic beverages suchas beer may also be a factor.

Primary

• No recognized cause

• Hypoxanthine

phosphoribosyltransferas

e deficiency

• Increased phosphoribosyl

pyrophosphatase activity.

Secondary

• Hereditary fructose

intolerance

• Myeloproliferative

disease

• Lymphoproliferative

disease

• Hemolyticc anemia

• Drugs: Low-doses salicylate,

diuretis, pyrazinamide,

ethambutol, nicotinamide, etanol

• Hyperuricemia does not represent a disease.

• Is not an specific indication for therapy.

• The finding of hyperuricemia is an indication to determine

its cause.

• The hyperuricemia of individuals who excrete uric acid

above this level while on a purine-free diet is due to purine

overproduction, whereas it is due to decreased excretion in

those who excrete lower amounts on the purine-free diet.

• The most recognized complication of hyperuricemia is gouty

arthritis

• Nephrolithiasis

• Urate Nephropathy

• Uric Acid Nephropathy

• 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

• Deposits of monosodium urate crystals surrounded by a giant

cell inflammatory reaction in the medullary intrerstitium and

pyramids.

• Clinically: silent or cause proteinuria, hypertension and renal

insufficiency

• Precipitation in renal tubules and collecting ducts

cause obstruction to urine flow.

• Following sudden urate overproduction and marked

hyperuricaciduria:• Dehydration and acidosis

• Lymphoma

• Cytolytic therapy

Crystal-induced arthritides

• MSU (monosodium urate)

• CPPD (calcium pyrophosphate dihydrate)

• HA (calcium hydroxyapatite)

• Calcium oxalate (CaOx)

• Affecting middle-aged to elderly men.

• Women represent only 5 to 17% of all patients.

• Associated with an increased uric acid, hyperuricemia, episodic acuteand chronic arthritis, and deposition of MSU crystals in connectivetissue 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 patientswith ethanol abuse as well as in postmenopausal women.

• “Disease of Kings”• Alexander the Great

• King Henry VIII

• Benjamin Franklin

• Alexander Hamilton

• Voltaire

• The metatarso phalangealjoint of the first toe is ofteninvolved.

• Ankles, and knees are alsocommonly affected.

• In elderly patients, fingerjoints may be inflamed.

• The first episode of acute gouty

arthritis frequently begins at

night.

• With dramatic joint pain and

swelling.

• Joints rapidly become warm, red,

and tender, and the clinical

appearence often mimics a

cellulitis.

• Early attacks tend to subside

spontaneously within 3 to 10

days.

• Most of the patients do not have

residual symptoms until next

episode.

• After many acute attacks, a portion of gouty patients

may presents with a chronic nonsymmetric synovitis.

• Causing potential confusion with rheumatoid

arthritis.

• More rarely, the disease will manifest as inflamed or

noninflamed periarticular tophaceous deposits in the

absence of chronic synovitis.

• Presentation:

• Tophus: urate deposits

• Fingers>olecranon bursae>forearm>achillestendon>knees>wrists>hand

• Late complication of gout, uncommon in the general population

• Complications:

• Joint deformities and destruction

• Pain

• Damage to surrounding tissue

• Nerve compression

• 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.

• Acute attack:

• Anti-inflammatory drug:

• Colchicine

• Nonsteroidal anti-inflamtory drugs

• Glucocorticoids

• Depending on the age of the patient and comorbid conditions.

• Uricosuric agents

• Probenecid

• Allopurinol

•Also known as Nyhan's syndrome, Kelley-Seegmiller syndrome and Juvenile gout

•It is a hereditary disorder of purine metabolism, characterized by menntalretardation, self-mutilation of the fingers and lips by biting, impaired renalfunction, and abnormal physical development.

• It is a recessive disease that is linked to the X chromosome

• It is caused by a deficiency of the enzyme hypoxanthine-guaninephosphoribosyltransferase (HPRT)

The hyperuricemia in Lesch-Nyhan patients is ex-plained, at least in part, on the basis of intracellular accu-mulation of PRPP leading to increased purine nucleotidebiosynthesis de novo and increased production of uric acid.

Overproduction of uric acid

• Urate crystal formations, which look like orange sand, are deposited in diapers of the babies

• Kidney stones

• Blood in the urine

• Dysphagia (difficulty swallowing)

• Swelling of the joints

• Vomiting

Behavioral Abnormalities

• Impaired cognitive

functon

• Self-mutation

• Aggression/Impulsion

Behavioral Abnormalities

self-mutilation of the lips by biting

Behavioral Abnormalities

self-mutilation of the fingers by biting

Overproduction and accumulation of uric acid

• There may be a family history of this condition.

• The doctor will perform a physical exam. The exam may show:

• Overexaggerated reflexes

• Spacity

• Blood and urine tests may reveal high uric acid levels. A skin biopsy may show decreased levels of the HGP enzyme.

• Prenatal diagnosis is possible by DNA testing of fetaltissue drawn by amniocentesis or chorionic villussampling (CVS)

-LNS itself cannot be treated

-Only the symptoms of LNS can be treated.

-The drug allopurinol may be used to control

excessive amounts of uric acid.

-Kidney stones can be treated with lithotripsy

-To help reduce some of the problem behaviors and

neurological effects of LNS :

Diazepam (Diastat, Valium)

Haloperidol (Haldol)

Phenobarbital (Luminal)

-The prognosis for LNS is poor because there are no

treatments for the neurological effects of the syndrome.

-Persons with this syndrome usually require assistance

walking and sitting and generally need a wheelchair to get

around.

-The build-up of excessive uric acid in the body causes painful

episodes of self-mutilation and may result in severe retardation

and death.

• Adenosine deaminase (ADA) is an essential enzyme of purine metabolism and is highly conserved throughout phylogeny.

• investigations indicated that ADA deficiency accounts forapproximately 20% of cases of human SCID and that it is the most severe of the immunodeficiency diseases, affecting both cell-mediated and humoral immunity (Buckley et al., 1997; Hershfieldand Mitchell, 2001).

• Soon after their discovery that defects in ADA were associated with immunodeficiency, Giblett and colleagues examined other immunodeficient individuals for deficiencies in purine catabolic enzymes and found that defects in purine nucleoside phosphorylasealso result in immunodeficiency disease.

molecular weight of 41 kDa .

adenosine aminohydrolase, EC 3.5.4.4

monomeric, zinc-dependent enzyme.

encoded by 12 exons.

ADA gene is 32 kb.

The gene is on chromosome 20q13.11.

mostly an intracellular enzyme.

found throughout body.

part of the purine catabolism pathway.

most active in lymphocytes.

functions in eliminating adenosine and deoxyadenosine.

• Associated with the loss of ADA activity ,The thymus is absent or small and dysplastic in ADA-deficient individuals (Borzy et al., 1979).

• They have severely reduced numbers of peripheral T, B, and natural killer (NK) cells(Buckley et al., 1997).

• ADA-deficient SCID is the only immunodeficiency in which all three cell types are severely reduced in number.

• Autosomal recessive disease .

• In the absence of ADA lymphocytes are destroyed.

• Deoxyadenosine and deoxyguanosine are toxic to human lymphoid cells in culture and have been implicated in the pathogenesis of the immunodeficiency states associated with adenosine deaminase and purine nucleoside phosphorylase deficiency, respectively.

• deoxyadenosine is not destroyed, is converted to dAMP and then into dATP.

• There marked increase in cellular concentrations of dATP due to the lack of conversion of excess deoxyadenosine to deoxyinosine and hypoxanthine .

• dATP is a potent feedback inhibitor ofdeoxynucleotide biosynthesis and DNA replication

• Diagnosis is usually made at 6 months of age (Kalman et al., 2004).

• Before this time, newborns are relatively protected by the mother’s

antibodies in the colostrum.

• Frequent infections in babies include oral candidiasis (thrush) and persistent

diarrhea. Growth impairment and/or interstitial pneumonitis can also occur

(Fischer, 2000).

• They do not respond to usual therapy.

• SCID patients have recurrent viral, fungal, and bacterial infections that

usually occur in the respiratory tract and gut (Fischer, 2000).

• SCID patients often do not respond to the antibiotics used to treat bacterial

infections.

Diffuse rash in an

infant with ADA

deficiency.

Lymphopenia

Defect in T-cell activation

low serumimmunoglobulins

beware – antibody transferred from mother

Elevated IgE

Peripheral eosinophilia

Elevated plasma adenosine

Elevated plasma and urine 2-deoxyadenosine levels

Elevated dATP levels in erythrocytes.

• A successful biochemical approach for the treatment of ADA deficiency involves the use of enzyme replacement therapy wherein a polyethylene glycol–modified form of bovine ADA (PEG–ADA) is provided to patients by twice weekly intramuscular injection (Hershfield et al., 1993).

gene therapy

• the hope is that efficient transfer of a recombinant ADA gene into hematopoietic cells will result in the outgrowth of a genetically repaired immune system.

• For these and other reasons, ADA gene therapy studies were the first to use ex vivo approaches to stably introduce new genetic information into patients.