Hyperuricemia and Gout

Hyperuricemia vs. Gout

• Hyperuricemia refers to elevated uric acid levels in the blood, surpassing the normal range of 3-7 mg/dL.
• Gout is a clinical condition resulting from hyperuricemia where uric acid precipitates, leading to inflammation and arthritis.
• Hyperuricemia does not always progress to gout; kidney function can eliminate excess uric acid.
• Some individuals with uric acid levels above the normal range (e.g., 9.6 mg/dL) may not develop gout.
• Conversely, individuals with uric acid levels within or slightly above the normal range (e.g., 6.2-6.5 mg/dL) can still experience gout.

Uric Acid Background

• Uric acid is the end product of purine metabolism.
• Purines, specifically adenine and guanine, originate from DNA and RNA.
• Xanthine oxidase converts adenine and guanine into xanthine and hypoxanthine, which are then converted into uric acid.
• Humans and higher primates lack the uric acid oxidase enzyme (urate oxidase), found in lower animals.
  • This enzyme converts uric acid into soluble substances like carbon dioxide, water, and allantoin.
• Pharmaceutical research is exploring genetically engineered versions of uric acid oxidase from animals for use in humans with resistant hyperuricemia or gout.
• Once formed in humans, uric acid must be excreted via the kidneys.

Causes of Increased Uric Acid Formation

• High purine intake:
  • Consumption of animal proteins such as meat, liver, and kidneys, which are rich in DNA and purines.
    • Gout was historically known as "the disease of kings" due to its association with the diets of wealthy individuals who consumed large amounts of meat.
  • Plant-based proteins (e.g., beans, lentils) also contain purines, but in moderate amounts.
• Treatment of malignancy:
  • Cancer treatments that destroy cancer cells release DNA, which is converted into uric acid.
  • This condition is referred to as tumor lysis syndrome.
  • Can lead to hyperuricemia and related complications
• Lesch-Nyhan syndrome:
  • Rare, genetic disorder linked to the X chromosome.
  • Characterized by various manifestations
  • Neurological issues and motor impairments.
  • Causes overproduction of uric acid.

Uric Acid Excretion

• Uric acid is mainly excreted through the kidneys.
  • About 80% of uric acid is kidney filtered.
• In the proximal convoluted tubule, organic acid transporter (OAT) proteins facilitate uric acid excretion into the urine.
• Another transporter reabsorbs approximately 90% of the uric acid, reducing the amount excreted.
• This reabsorption suggests that uric acid has an important physiological function.
  • Uric acid functions as a powerful antioxidant.
  • Contributes to 50% of the body's defense against oxidative stress.
  • Because the human body cannot produce ascorbic acid (vitamin C), uric acid serves as its replacement to combat oxidative stress.
• Issues with renal uric acid excretion accounts for 90% of hyperuricemia cases.
• Medications, like aspirin and diuretics, can interfere with uric acid excretion by competing with transporters in the kidney.
  • Aspirin and thiazide diuretics can interfere with uric acid excretion, increasing uric acid levels.
  • The effect is due to competition for common organic acid transporters.
  • High doses of aspirin may increase uric acid excretion by inhibiting reabsorption, but this requires impractical dosages.

Gout Development

• Excess uric acid in the body will sometimes form crystals and deposit around the joints:
  • These crystals trigger irritation.
  • Creates inflammation.
  • Uric acid crystals accumulate in periarticular regions, synovial membranes, and tissues.
• The uric acid turns into monosodium urate crystals, and look like needles under a microscope.
  • A polarized light is used
• The result is pain when moving the joints, especially in the big toe (first metatarsophalangeal joint).
• The chronic irritation is from monosodium urate crystals.
• Immune cells (microphages) attempt to phagocytose the uric acid crystals, which they see as foreign bodies that must be removed.
  • Microphages take up the uric acid crystals.
  • Macrophages lack the enzyme (uricase) to break it down.
  • Then the macrophage ruptures and releases cytokines.
• When cytokines are released they case an exaggerated inflammation.
  • These released cytokines induce an acute inflammatory response.
  • Includes substances with interleukin and prostaglandin.
• Patients with gout may experience:
  • Chronic irritation or pain in the joints (chronic gout)
    • Exacerbated by movement or warm conditions
  • Severe acute pain due to an acute gouty attack or arthritis

Gout Medications

• Medications can be divided into 2 types:
  • Hypouricemic drugs - Lower the uric acid level
  • Anti-inflammatory drugs - Target inflammation.

Hypouricemic Drugs

• Three types:
  • Uricosuric drugs:
    • Increase uric acid excretion through the kidneys.
    • Example: Probenecid
  • Xanthine oxidase inhibitors:
    • Prevent the production of uric acid by inhibiting the xanthine oxidase enzyme.
    • Example: Allopurinol
  • Uric acid metabolism enhancers:
    • Increase uric acid breakdown in the body.
    • Accomplished by administering the uricase enzyme from animals.

Probenecid

• Uricorsuric drug that increases uric acid secretion
• Acts on a translocator in the kidney
• This has a biphasic action, meaning two opposite way depending on dosage
• SSmall doses:
  • (e.g., one 500 mg tablet per day) inhibits uric acid excretion, increasing uric acid retention.
• Large doses:
  • (two or three 500 mg tablets per day) inhibit uric acid reabsorption, increasing uric acid excretion.
• In addition to treating gout, probenecid can be used to inhibit the excretion of other acidic drugs (e.g., penicillin) to prolong their effects within the body.
• Common side effects of probenecid include GI upset and irritation.
• Rare side effect is kidney failure (interstitial nephritis)
• Precautions during use:
  • Probenecid is not appropriate for use during an acute gout attack because it mobilizes uric acid stores and exacerbates inflammation.
  • Patients should drink plenty of fluids.
  • Alkylates the Urine to facilitate uric acid secretion
  • Avoid aspirin, as it promotes uric acid retention.

Allopurinol

• Structure analog of uric acid that inhibits xanthine oxidase.
• Prevents the conversion of hypoxanthine and xanthine to uric acid
• Allopurinol has a short half life
• Converts to oxypurinol, a metabolite that is responsible for xanthine oxidase inhibition for up to 24 hours.
• Due to the 24 hour effect, allopurinol is recommended with a single dosage
• Allopurinol is used to counter chronic conditions (gout)
• Primary goal is achieving level below 5mg/dL
• Allopurinol can be used for:
  • Gout
  • Patients with tumor lysis
  • Lesch-Nyhan syndrome
• Side effects / precautions:
  • Causes a skin reaction
    • Severe reactions can be lethal if the patient obtains Stevens-Johnson Syndrome _ Same as probenecid, do not give when a patient is having an acute attack of gout.
• Three drugs that should not be taken with this drug:
  • Six-mercaptopurine (cancer)
  • Azathioprine (autoimmune)
  • Theophylline (asthma)

Pegloticase

• Treats severe gout cases
• Not manageable with allopurinol
• In severe cases: Uric acid makes lumps (gouty tophi) or uric acid enters the Kidney where is crystalizes.
• Treatment = Uricase (Uric acid metabolism enhancers), the enzymes that breaks down uric acid
• From the Pig engineered (Rasburicase)
  • But Rasburicase is short - so Peglotocase!
    • PEG = Polyethylene Glycon
• The dose lasts for 2 weeks in the body.

Acute Gout Treatment

• Do not use Hypouricemic drugs
• If there is an acute inflammatory attack = cortisone or steroids

Colchicine

• Plant Alkaloid that acts on Microtubules
• Interferes with spindle, so NO replication - Not good for cancer cells here
• Mostly used with Neturophiles in Macrophages around the Joint - Stops the ability to move and extract the proteins
• For treatment, take 2 pills together with a 1 hour gap, and take the third pills in 12 hours
• Colchicine is also used to stop production of amyloid in Familial Mediterranean Fever and inflammation
• Bad points = VERY Toxic and Dangerous - 1. Common is DIARRHEA since the drug stops cells development in intestines - II. Rarer is Baldness or weak muscles - III. BONE MARROW is blocked, so not blood made = MORTALITY rate! Abastic Anemia.
• DO NOT USE in acute Inflammations - Use Endomethacin and Naproxen instead, since those have are recommended for pain.
• Take Cortisone injections when that happens.