gout biochem

7/31/2019 Gout Biochem

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GoutBy

AleassaArun

Ilemona

Marissa


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History

The word goutwas initially used by Randolphus ofBocking, around 1200 AD. It is derived from the Latinword gutta, meaning "a drop" (of liquid).

Historically, it has been referred to as "the king ofdiseases and the disease ofkings or "rich man'sdisease".

The first documentation of the disease is from Egypt in2,600 BC in a description of arthritis of the big toe.

Antonie van Leeuwenhoek described the microscopicappearance of uric acid crystals in 1679.

In 1848 English physician Alfred Baring Garrod realizedthat this excess uric acid in the blood was the cause of

gout.


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Definition Gout is a disorder characterized by high levels of uric acid( end

product of purine catabolism) as a result of underexcretion oroverproduction of UA.

Metabolic Disorder underlying gout is hyperuricemia.

Defined as 2 SD above mean usually 7.0 mg/dL. This

concentration is about the limit of solubility for(monosodium urate) MSU in plasma. At higher levels, theMSU is more likely to precipitate in tissues.

Hyperuricemia leads to the deposition of uric acid salts and

crystals in and around joints and soft tissues or crystallizationof uric acid in the urinary tract.

Major route of disposal is renal excretion

Humans lack the enzyme uricase to break down uric acidinto more soluble form.


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Epidemiology

Most common of microcrystalline arthropathy. Incidence hasincreased significantly over the past few decades.

Affects about 2.1million worldwide

Peak incidence occurs in the fifth decade, but can occur at any

age Gout is 5X more common in males than pre-menopausal

females; incidence in women increases after menopause.After age 60, the incidence in women approaches the rate inmen.

People of South Pacific origin have an increased incidence.


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Pathophysiology

Primary gout is caused byinborn defects in purinemetabolism or inheriteddefects of the renal tubular

secretion of uratemonohydrate crystals (tophi).

Secondary gout is caused byacquired disorders that resultin increased turnover of

nucleic acids, by defects inrenal excretion of uric acidsalts, and by the effects ofcertain drugs


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HYPERURICEMIA & GOUT 5-phosphoribosyl-1-pyrophosphate synthetase (PRS )superactivity and

hypoxanthine-guanine phosphoribosyl transferase ( HPRT) deficiency: twoinborn errors associated with hyperuricemia and gout

Hyperuricemia caused by

Overproduction

Underexcretion

No Gout w/o crystal deposition mutations in theX-linked PRPP synthetase gene result in the enzyme

having an increased Vmax resulting in over production.

PRS superactivity; increased PP-Rib-P levels due to overproduction (noapparent decreases in purine nucleotide concentrations)

HPRT deficiency: PP-Rib-P accumulates due to underutilization of this

salvage reaction Increased PP-Rib-P availability in both cases results in activation of

AmidoPRT and acceleration of purine nucleotide and uric acid synthesis


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Asymptomatic hyperuricemia

Very common biochemical abnormality Defined as 2 SD above mean value

Majority of people with hyperuricemia never develop symptoms of uricacid excess

Acute Intermittent Gout (Gouty Arthritis)

Episodes of acute attacks. Symptoms may be confined to a single joint orpatient may have systemic symptoms.

Intercritical Gout

Symptom free period interval between attacks. May have hyperuricemiaand MSU crystals in synovial fluid

Chronic Tophaceous Gout

Results from established disease and refers to stage of deposition of urate,inflammatory cells and foreign body giant cells in the tissues. Depositsmay be in tendons or ligaments.

Usually develops after 10 or more years of acute intermittent gout.

GOUT: A Chronic Disease of 4 stages


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Associated Conditions

Cardiovascular Disease

Pagets disease

Arthritis- rheumatoid and osteoarthritis Septic Arthritis

Metabolic syndrome


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Heredity Drug usage

Renal failure

Hematologic Disease

Trauma Alcohol use

Psoriasis

Poisoning

Obesity

Hypertension

Organ transplantation

Surgery

Predisposing

Factors


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Presenting Symptoms

Systemic: fever rare but patients mayhave fever, chills and malaise

Musculoskeletal: Acute onset ofmonoarticular joint pain. FirstMTP(metatarsophalangeal ) mostcommon. Usually affected in 90% of

patients with gout. Other joints knees,foot and ankles. Less common in upperextremities Postulated that decreased solubility of MSU

at lower temperatures of peripheralstructures such as toe and ear

Skin: warmth, erythema and tensenessof skin overlying joint. May have pruritusand desquamation

GU: Renal colic with renal calculiformation in patients with hyperuricemia


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The presence of characteristic urate crystals in the joint fluid, or a tophusproved to contain urate crystals by chemical means or polarized lightmicroscopy, or the presence of 6 of the following 12 clinical, laboratory,and radiographic phenomena:

1. More than one attack of acute arthritis

2. Maximum inflammation developed within 1 day

3. Monoarthritis attack4. Redness observed over joints

5. First metatarsophalangeal joint painful or swollen

6. Unilateral first metatarsophalangeal joint attack

7. Unilateral tarsal joint attack

8. Tophus (proven or suspected)

9. Hyperuricemia

10. Asymmetric swelling within a joint on x ray/exam

11. Subcortical cysts without erosions on x ray

12. Monosodium urate monohydrate microcrystals in joint fluid during attack

13. Joint fluid culture negative for organisms during attack

1977 ACR criteria for acute gout


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Diagnostic Studies Uric Acid

Limited value as majority ofhyperuricemic patients will neverdevelop gout

Levels may be normal during acuteattack

CBC

Mild leukocytosis in acute attacks, butmay be higher than 25,000/mm

ESR

mild elevation or may be 2-3x normal

24hr urine uric acid

Only useful in patients being

considered for uricosuric therapy or ifcause of marked hyperuricemia needsinvestigation

Trial of colchicine

Positive response may occur in othertypes of arthritis to include

pseudogout.

Definitive diagnosis onlypossible by aspirating and

inspecting synovial fluid ortophaceous material anddemonstrating MSU crystalsPolarized microscopy, thecrystals appear as bright

birefringent crystals that areyellow (negativelybirefringent)

Diagnosis


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Differential Diagnosis

Trauma Infections

septic arthritis, gonococcalarthritis, cellulitis

Inflammatory Rheumatic arthritis, Reiters

syndrome, Psoriatic arthritis

Metabolic pseudogout

Miscellaneous Osteoarthrtis

RA vs Gout

Tophi nodules

can sometimes

be mistaken for

RA nodule


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Treatment Goals

Gout can be treated without complications. Therapeutic goals include

terminating attacks providing control of pain and inflammation preventing future attacks preventing complications such as renal stones, tophi,

and destructive arthropathy

Acute Gout Treatment NSAIDs

Colchicine Corticosteriods ACTH Intra-articular injection with steroids


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Non- Pharmacologic Treatments

Immobilization of Joint

Ice Packs

Abstinence of Alcohol

Consumption can increase serum urate levels by increasing uric acid

production. When used in excess it can be converted to lactic acidwhich inhibits uric acid excretion in the kidney

Dietary modification

Low carbohydrates

Increase in protein and unsaturated fats

Decrease in dietary purine-meat and seafood. Dairy and vegetables donot seem to affect uric acid

Bing cherries and Vitamin C


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Prophylaxis

Urate Lowering drugs

Used for documented urate overproduction Goal is for serum urate concentration to 6mg/dL or less Start of therapy can precipitate acute attack; therefore, may

need to use colchicine as a long as six months Xanthine oxidase inhibitors

Allopurinol: blocks conversion of xanthine to uric acid. works

for underexcretors and overproducers. Start typically 300mg/day and titrate weekly 100mg/day

until optimal urate levels achieved. Start lower doses with renally impaired patients

Uricosuric drugs Probenecid or Sulfinpyrazone: increase renal clearance of

uric acid by inhibiting tubular absorption Side effects may prohibit use-GI and kidney stones Need measurement of 24hr urine in anyone for whom

Probenecid therapy is initiated


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Newer Therapies

Uricase Enzyme that oxidizes uric acid to a more soluble form

Natural Uricase from Aspergillus flavus and Candida utilisunder investigation

Febuxostat

New class of Xanthine Oxidase inhibitor More selective than allopurinol

Little dependence on renal excretion

Losartan

ARB given as 50mg/dL can be urisuric. When given withHCTZ, it can blunt the effect of the diuretic and potentiateits antihypertensive action

Fenofibrate

Studies note when used in combo with Allopurinol

produced additional lowering of the urate


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References

Klippel, JH.Primer on Rheumatic Diseases. 12th ed. ArthitisFoundation 2001; 307-323.

Schumacher HR, Chen LX. Newer Therapeutic Approaches:Gout. Rheumatic Disease Clinics of North America 2006;32.

Pittman, JR, Bross, MH. Diagnosis and Management of Gout.American Family Physician 1999;59

Monu JU, Pope TL. Gout: a clinical and radiologic review.Radiologic Clinics of North America. 2004;42

Goldman. Cecil Textbook of Medicine. 22nd ed. W.B. SaundersCompany 2004;

Shen S, Wolfe R. Gout. Emergency Medicine Clinical Reviews.2004

http://en.wikipedia.org/wiki/Gout
http://en.wikipedia.org/wiki/Gouthttp://en.wikipedia.org/wiki/Gouthttp://en.wikipedia.org/wiki/Gout

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