Epidemiology of Gout

about 1% of western population suffers gout

7-9:1 male predominance

classically assoiciated with "indulgent" lifestyle--rich food and drink (especially red meat and alcohol) and smoking

associated with obesity, hypertension, and hyperlipidemia

Gout Pathology

arthritis, nephropathy

chronic underlying hyperuricemia w/acute flares of arthritis, chronic and/or acute renal damage

monosodium urate crystal deposition in joints, cartilage, renal parenchyma, and subcutaneous tissues (tophi)

crystal formation encouraged by high levels of uric acid, low pH, low temperature, possible tissue factors

Acute Gout

arthritis flare, usually one joint red and inflammed, often the great toe (podagra)

mediated by monosodium urate crystal precipitation in synovial space, crystals often detectable with synovial fluid aspiration

monosodium urate crystals are needle shaped and yellow if parallel to slow wave

Uric Acid Handling at Nephron

uric acid=weak organic acid

freely filtered at glomerulus

simultaneously secreted and reabsorbed from proximal tubule--only about 10% of filtered uric acid is excreted

reabsorption by URAT-1 protein in organic anion transporter family (competition for transporter with other organic acids)

Kidney manifestations of Gout

(extra-articular damage)

1. Gouty nephropathy: chronic renal insufficiency due to deposition of crystals in parenchyma over time, leads to hypertension

2. Obstructive nephropathy caused by acute intratubular crystal precipitation-->acute renal failure (acute tubular necrosis)

3. Nephrolithiasis--formation of kidney stones in renal pelvis/ureter

Hyperuricemia

serum uric acid >7mg/dL in men

>6mg/dL in women

may be asymptomatic but predisposes to gout

overproduction or underexcretion of uric acid

80-90% of gout patients are (genetically predisposed) underexcretors

Causes of Underexcretion of Uric Acid

drugs: diuretics, aspirin, ethambutal, L-dopa, cyclosporine, alcohol, nicotine

medical disorders: especially poorly controlled diabetes

idiopathic renal retention of uric acid

renal damage (glomerular or tubular)

high levels of competing organic acids like lactate and beta hydroxybutyrate

Causes of Overproduction of Uric Acid

increased rate of de novo purine (adenine and guanine) synthesis

enzyme defects: decreased HGPRT activity (Leish-Nyan Syndrome) or increased PRPP synthetase activity

increased nucleic acid synthesis due to increased rate of cellular turnover, i.e. polycythemias or tumor lysis syndrome (myeloproliferative/lymphoproliferative disorders and cancer chemotherapy)

Podagra

acute gouty inflammation of the big toe

extremely painful

joint is red and warm, must distinguish from septic arthritis

initial presentation of gout about half the time

Tophi

subcutaneous nodules comprised of uric acid crystals 

found in patients with chronic gout

Inflammatory Mechanism of Gouty Arthritis

synoviocytes and macrophages attempt to phagocytose monosodium urate crystals in joint

crystals rupture phagocytic cell membranes --> inflammatory cytokine release: IL-1, LTB4, prostaglandins)

cytokines attract and activate neutrophils and macrophages which attempt phagocytosis of crystals

cycle repeats with amplifying tissue damage and inflammation

Purine Metabolism

1. phosphoribosylpyrophosphate synthestase (PRPP synthetase) converts ribose 5-P and ATP-->PRPP and glutamine       RATE LIMITING step

PRPP synthetase overexpression--increased uric acid levels ultimately

intermediate steps (PRPP-->5-phosphoribosyl-1-amine  -->inosinic acid)

2.  cellular and dietary purine nucleotides are in equilibrium with inosinic acid 

3. Inosinic acid-->Inosine

4. Inosine is in equilibrium with Hypoxanthine

5. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) converts hypoxanthine-->inosinic acid (allowing salvage synthesis of purines)

HGPRT deficiency=Leish-Nyan syndrome and leads to elevated uric acid levels

6. and 7. Xanthine oxidase converts hypoxanthine to xanthine to uric acid

Xanthine Oxidase Inhibitors

increase levels of hypoxanthine, leading to increased HGPRT activity and increased purine salvage

decrease levels of uric acid

Allopurinol (and active metabolite oxypurinol)

Febuxostat

treatment of choice for chronic gout management

Uricosuric Agents

Inhibit uric acid reabsorption at kidney

decrease serum urate concentration

by increasing uric acid excretion may cause crystal precipitation in urine and stone formation in the kidneys--use with caution in renal patients, advise patients to increase water intake

Probenecid and Sulfinpyrazone

Aspirin Dual Effect

low doses of acetylsalicylic acid can cause hyperuricemia (selective inhibition of uric acid secretion at nephron)

high doses can decrease serum uric acid levels by interfering with reabsorption of uric acid at nephron (aspirin acts as a uricosuric aagent at higher doses)

Colchicine

older drug used for acute gouty arthritis, could improve symptoms within 1 hour and resolve flare-up by 12 hours, oral or IV

largely replaced by NSAIDs (safer)

MOA: binds to intracellular protein tubulin, prevents polymerization into microtubules, lack of microtubule remodeling inhibits migration and phagocytosis attempts by leukocytes responsible for inflammation of acute gout

toxic effects (overdose): abdominal pain, nausea, and diarrhea--discontine colchicine immediately!

Indomethacin (Indocin)

NSAID used to treat acute gouty arthritis

MOA: blocks prostaglandin synthesis, inhibits crystal phagocytosis, reduces inflammation

Naproxen (Naprosyn, Anaprox, Aleve)

NSAID used to treat acute gouty arthritis

MOA: inhibits phagocyte migration and crystal phagocytosis

Sulindac (Clinoril)

Probenecid (Benemid, Probalan)

Uricosuric agent (inhibits uric acid reabsorption by kidney) used to control hyperuricemia in chroic, tophaceous gout

developed in '50s to prolong penicillin levels

toxicity: GI irritation, mild skin rash, renal damage due to crystal precipitation in urine

precautions: increase water intake and slowly titrate up to desired dose to prevent tubular damage and stone formation in kidneys, avoid in patients with renal failure

Rasburicase (Elitek)

recombinant uricase, an enzyme found in most non-human mammals which converts uric acid to the more solluble compound allantoin

new drug used to treat hyperuricemia due to tumor lysis syndrome

IV, single course only! due to high risk of anaphylaxis

Adverse rxns: allergy/anaphylaxis

Contraindicated for patients with glucose-6-phosphate dehydrogenase deficiency b/c can cause hemolysis and methemoglobinemia

Sulfinpyrazone (Anturane)

Uricosuric agent (inhibits uric acid reabsorption by kidney) used to control hyperuricemia in chronic, tophaceous gout

toxicity: GI irritation (10-15%), skin rash with fever, renal damage due to crystal precipitation in urine

precautions: increase water intake and slowly titrate up to desired dose to prevent tubular damage and stone formation in kidneys, avoid in patients with renal failure

Allopurinol (Zyloprim)

purine xanthine oxidase inhibitor used to treat gouty nephropathy, chronic tophaceous gout, renal urate stones, and hyperuricemia secondary to hematologic disorders or cancer chemotherapy

drug of choice for prevention in chronic gout, oral

MOA: inhibits xanthine oxidase, decreasing levels of uric acid, causing more xanthine and hypoxanthine to be excreted in the urine (more soluble vs. uric acid), diverting hypoxanthine to purine salvage pathways, also decreases PRPP levels intracellularly

active metabolite oxypurinol (alloxanthine) also inhibits xanthine oxidase

IMPORTANT INTERACTIONS: increased toxicity if combined with the immunosuppresive/chemotherapeutic drugs 6-mercaptopurine and azathioprine, metabolism inhibited by oral anticoagulants, increased risk of rash if combined with ampicillin

Toxicity: allergic skin rxn.,  GI intolerance

Precautions: avoid in patients using 6-mercaptopurine or azathioprine or reduce dosages

Febuxostat (Uloric)

newer non-purine xanthine oxidase inhibitor used to treat gouty nephropathy, chronic tophaceous gout, renal urate stones

oral, potent selective xanthine oxidase inhibitor

well tolerated in patients who can't tolerate allopurinol

Adverse rxns: diarrhea, nausea, vomiting, increased liver transaminases

DRUG INTERACTIONS: increased toxicity with 6-mercaptopurine and azathioprine like allopurinol

Pegloticase (Krystexxa)

PEGylated uric acid specific uricase

uricase=enzyme which converts uric acid to more soluble allantoin in most non-human mammals

newer drug for treatment of chronic gout in patients unresponsive to or contraindicated for traditional therapy  i.e. a renal transplant pt. on azathioprine (allopurinol and fevuxostat interact with azathioprine, probenecid and sulfinpyrazone can damage kidney)