Gout and Hyperuricemia

Gout

• Gout is an inflammatory disease
• It is characterized by uric acid or urate crystal deposits in joints, soft tissues like cartilage, and renal tissues like the glomeruli
• These deposits cause severe arthritis or joint pain

Tophi/Tophaceous Gout

• These are chronic complications
• They present as large, visible bumps or nodules in soft tissue
• Consist of uric acid crystals which leads to pain and inflammation

Other Complications of Hyperuricemia

• Uric acid nephrolithiasis, which means kidney stones
• Nephropathy

Gouty Arthritis

Asymptomatic Hyperuricemia

• Elevated serum urate levels indicate this, specifically levels higher than 400 umol/L
• There are no clinical manifestations present

Gouty Flare

• This is a quick onset of excruciating pain and inflammation
• It commonly happen in the night or early morning
• 85% of attacks start off as monoarticular, and the big toe is the most common site
• It is also known as a gout attack or flare up

Intercritical Gout

• This phase occurs after the first gout flare
• The individual is asymptomatic during this time
• The main goal is prophylaxis of another gout flare

Chronic Gouty Arthritis

• Typically develops 12 years after onset, with only 2% of patients experiencing severe crippling disease
• Therapy aims to control pain and inflammation

Pathophysiology

• Uric acid is the final waste product of purine metabolism and is excreted renally
• Gout is a condition where excess uric acid accumulates, forming urate crystals
• These crystals deposit in joints, soft tissues like tendons or cartilage, or renal tissues like glomeruli
• Risk can be increased by overproduction of uric acid or under-secretion of uric acid
• Overproduction: higher purine intake, abnormal enzyme function, and dysregulation
• Under-secretion: reabsorption of uric acid in the kidney potentially due to dehydration

Foods High in Purines

• Red meats
• Beer
• Fish
• Shellfish

Risk Factors for Hyperuricemia and Gout

• Excess alcohol intake
• Atherosclerosis
• Chronic kidney, glomerular, and interstitial renal disease
• Diabetes
• Hyperlipidemia
• Hypertension
• Ischemic heart disease
• Lead intoxication
• Metabolic syndrome
• Myeloproliferative disorders and some cancers
• Obesity
• History of urolithiasis
• Genetic and/or acquired causes of uric acid production, although this is rare

Goals of Therapy

• Terminate the acute attack of arthritis
• Prevent recurrence
• Prevent or reverse complications
• Treat associated disorders
• Minimize side effects associated with drug therapy

Diagnosis

• Classical symptoms of gout is usually enough for accurate diagnosis
• Aspiration of synovial fluid is needed for atypical signs/symptoms,
• Screening for other comorbidities
• Radiographs are utilized for diagnosing chronic gout only
• Uric acid levels are important for monitoring, but not for diagnosis

Monitoring Uric Acid Levels

• People with high uric acid levels may have no symptoms and should not be treated
• Uric acid levels are normally elevated during an acute attack

Preventing Future Gout Attacks

• Avoid alcohol during acute attacks
• Limit intake to no more than 1-2 drinks daily for maintenance
• Maximum of 2 in men and 1 in women daily
• Avoid drinks high in fructose
• Avoid foods high in purines, such as sweetbreads, liver, and kidney
• Limit consumption of meat like beef, lamb, pork, and seafood
• Reduce intake of naturally sweet fruit juices, salt, table sugar, and sweetened beverages
• Encourage regular exercise to maintain a healthy weight
• Consume non-fat dairy products and vegetables, and stay hydrated
• Smoking cessation

Treating Gout

NSAIDs

• NSAIDs like indomethacin, naproxen, and ibuprofen are the most common
• All non-salicylate NSAIDs are effective
• Side effects: gastric ulcers, worsening hypertension, fluid retention, and edema
• Use with caution in those with cardiovascular disease, history of ulcers, or renal disease

Colchicine

• Antimitotic that mitigate the inflammatory response by neutrophils
• Can contribute to gout symptoms
• Side effects: Primarily GI, can cause nausea, vomiting, and diarrhea, this resolves with dose reduction and drug discontinuation),
• Chronic side effects include alopecia, bone marrow suppression, or neuropathy
• Colchicine is a major substrate of CYP3A4 and P-glycoprotein
• Avoid if CrCl is less than 30 mL/min

Corticosteroids

• These include Prednisone or prednisolone
• Can use via Intra-articular or intramuscular injection
• Useful for use in patients who cannot tolerate oral corticosteroids
• Side effects: hypertension, hyperglycemia, osteoporosis, mood changes, weight gain, or Cushing's Syndrome

Note

• Colchicine and NSAIDs are not recommended in severe renal impairment
• Oral corticosteroids should be considered for patients with severe renal impairment

Urate-Lowering Therapies

• These are therapies to lower uric acid to prevent flares in patients with established gout
• They are not indicated in asymptomatic hyperuricemia

Allopurinol

• Allopurinol (Xanthine Oxidase Inhibitor)
• 1st line agent: start at a low dose and titrate slowly to serum levels less than 360 µmol/L or to "target symptoms"
• Titration is key to prevent Allopurinol Hypersensitivity Syndrome AHS
• AHS is a severe potentially life-threatening condition that can present as Steven-Johnson's syndrome, toxic epidermal necrolysis, and systemic organ diseases
• Risk factors for AHS associated with allopurinol: initiating at high dose, renal impairment, positive for HLA-B*5801 allele (allele present in Han Chinese, Thai, Korea, and African American patients, or concomitant diuretic use

Febuxostat

• Febuxostat (Xanthine Oxidase Inhibitor)
• Used when allopurinol is ineffective, not tolerated, or due to patient specific factors
• Unlike allopurinol, it does not require renal dosage adjustments
• Increases the risk of CVD-related deaths in gout patients with established CVD

Urate-Lowering Therapy ULT

• Allopurinol is the 1st line therapy
• Start at a low dose then titrate to target
• Concomitant anti-inflammatory prophylaxis therapy (e.g., colchicine, NSAIDs, prednisone/prednisolone)s

The following patients are strongly recommended to start ULT prophylaxis

• Patients with more than 2 gout flares per year
• Patients with more than 1 subcutaneous tophi
• Evidence of radiographic damage seen with any imaging modality

The following patients are conditionally recommended to start ULT prophylaxis

• The decision to start is based on specific patient characteristics for example established CVD
• Patients with infrequent flares greater than 1 flare but less than 2 per year
• Patients with moderate-severe chronic kidney disease which is stage 3 or more
• Patients with serum uric acid levels more than 535 umol/L
• Patients with urolithiasis which means kidney stones
• When the decision is made that ULT is indicated while the patient is experiencing a gout flare, consider starting ULT during the gout flare versus starting ULT after the gout flare has resolved and must be advised that this can worsen the flare.