Asymptomatic Hyperuricemia Treatment Guidelines

Hyperuricemia treatment guidelines in the asymptomatic individuals are discussed here. Hyperuricemia is an elevated level of uric acid in the blood. The cut-off value for hyperuricemia is generally taken as a plasma uric acid levels greater than 7 mg/dl (416 micro mols/l).

However, most experts consider 6 mg/dl as the upper limits of normal.

Elevated uric acid levels affect almost one in every 4 adults. Persistent elevations of uric acid levels can result in:
  • Crystal deposition in the joints leading to Gout.
  • Nephrolithiasis
  • Urate nephropathy ( Acute urate nephropathy can be life-threatening if not treated immediately)

What causes increased uric acid levels in the blood?

Causes of elevated uric acid may be divided into either increased production or decreased excretion. Causes of increased uric acid production are summarized in the table below:
Inherited enzyme defects leading to purine overproduction (rare monogenic disorders)
Hypoxanthine-guanine phosphoribosyltransferase deficiency
Phosphoribosylpyrophosphate synthetase overactivity
Glucose-6-phosphatase deficiency (glycogen storage disease, type I)
Clinical disorders leading to purine and/or urate overproduction
Myeloproliferative disorders
Lymphoproliferative disorders
Malignancies
Hemolytic disorders
Psoriasis
Obesity
Tissue hypoxia
Down syndrome
Glycogen storage diseases (types III, V, VII)
Drug-, diet-, or toxin-induced purine and/or urate overproduction
Ethanol
Excessive dietary purine ingestion
Pancreatic extract
Fructose
Vitamin B12 deficiency
Nicotinic acid
Ethylamino-1,3,4-thiadiazole
4-amino-5-imidazole carboxamide riboside
Cytotoxic drugs
  Causes of hyperuricemia due to decreased urate clearance are summarized in the table below:
Clinical disorders
Chronic renal insufficiency of any form
Lead nephropathy (saturnine gout)
Effective volume depletion (eg, fluid losses, heart failure)
Diabetic or starvation ketoacidosis
Lactic acidosis
Preeclampsia
Obesity
Hyperparathyroidism
Hypothyroidism
Sarcoidosis
Chronic beryllium disease
Rare monogenic disorders causing a decreased uric acid clearance
Autosomal dominant tubulointerstitial kidney disease caused by UMOD pathogenic variants
Glomerulocystic kidney disease
Common variants in genes encoding transporters that regulate renal or gut uric acid clearance (numerous; genes with largest reported effect are shown)
SLC2A9
ABCG2
SLC17A1
SLC22A11
PDZK1
SLC16A9
SLC22A12
Drug- or diet-induced
Diuretics (thiazides and loop diuretics)
Cyclosporine and tacrolimus
Low-dose salicylates
Ethambutol
Pyrazinamide
Ethanol
Levodopa
Methoxyflurane
Laxative abuse (alkalosis)
Salt restriction
 

Association of asymptomatic hyperuricemia and Gout:

As the duration of untreated hyperuricemia gets prolonged or the individual has persistently high uric acid levels above 9 mg/dl, the risk of gout increases. Patients who develop gout usually have high levels of uric acid prior to the development of the joint disease. Similarly, uric acid can be elevated in intercritical gout flares, tophaceous gout, and chronic gouty arthritis. Tophi may occur in patients who have recurrent gout flares. Apart from patients with gout, tophi can also occur in elderly patients with asymptomatic hyperuricemia who are being treated with NSAIDs (Non-steroidal anti-inflammatory drugs) or glucocorticoid therapy.
The risk factors for hyperuricemia include:

Asymptomatic hyperuricemia and chronic Kidney disease:

High uric acid can result in chronic kidney disease. This is called urate nephropathy. However, the reverse is much more common. Kidney disease causes an elevation in uric acid level because it is not excreted. Patients who develop urate nephropathy usually have high levels of uric acid in the blood. In men, uric acid levels exceeding 13 mg/dl and in women, 10 mg/dl may result in urate nephropathy. Similarly, uric acid is elevated in kidney disease. However, in urate nephropathy, hyperuricemia is out of proportion to the stage of kidney disease. Elevated uric acid level out of proportion to the degree of renal insufficiency is defined as:
  • Uric acid levels exceeding 9 mg/dl in patients with a creatinine of 1.5 mg/dl or less.
  • Uric acid levels exceeding 10 mg/dl in patients with a creatinine of 1.5 - 2 mg/dl.
  • Uric acid levels exceeding 12 mg/dl in patients advanced renal disease.

Asymptomatic hyperuricemia and nephrolithiasis:

Individuals who excrete an excessive amount of uric acid in the urine are at increased risk of developing nephrolithiasis. The risk is as high as 50% if the 24-hour urinary excretion is 1100 mg/dl or more.

Asymptomatic hyperuricemia and non-crystal deposition diseases:

Apart from the well-known conditions, such as gout, urate nephropathy, and uric acid stones, other conditions have been associated with high uric acid levels. These include:
  • Hypertension
  • Cardiovascular diseases
  • Insulin resistance
  • Alzheimer's disease
  • Parkinson's syndrome

Evaluation of a patient with hyperuricemia ...

In general, most experts recommend evaluating patients with persistently raised uric acid levels above 8 mg/dl. Individuals with uric acid levels between 7 and 8 should be retested at 6 months interval. Individuals with uric acid levels below 7 mg/dl do not need further evaluation. Evaluation should include:
  • A thorough medical history and physical examination focusing on the following points:
    • History of gout or nephrolithiasis
    • Comorbid medical conditions
    • Medication history
    • Lifestyle
    • Family history
  • Laboratory investigations should include the following:
    • Blood CBC
    • Blood chemistry including:
        • Renal functions
        • Electrolytes
        • Calcium
        • Liver function
        • Urinalysis
Men younger than 25 years of age and women prior to menopause without an identifiable cause of hyperuricemia should undergo "Fractional excretion of uric acid (FEur)". This represents the percentage of uric acid excreted per unit of the GFR. FEur of greater than 10% signifies excessive uric acid excretion in patients with overproduction. FEur is done from a spot mid-day urinary sample. Some experts recommend doing a 24-hour urinary uric acid estimation. Levels exceeding 800 mg/dl in a 24-hour urinary sample identifies patients who excrete excessive amounts of uric acid and overproduce uric acid.
Most patients are over producers, under-excretors, or both.
Most individuals who overproduce uric acid consume purine-rich diets like meat and seafood. Patients who are labeled as over-excretors should be advised a diet deficient in purines for 3 days and the 24-hour urinary uric acid should be estimated. Individuals who have persistently high uric acid levels exceeding 670 mg/dl should be investigated for hereditary disorders (as mentioned in the table).

Management - Asymptomatic hyperuricemia treatment:

All individuals should be investigated for the underlying cause of hyperuricemia and treated accordingly. Patients without an identifiable cause and uric acid levels exceeding 8 mg/dl should be advised a non-pharmacological management plan.

Non-pharmacological treatment of hyperuricemia:

Patients should be advised:
  • weight reduction to ideal body weight
  • avoidance of sweetened beverages and alcohol
  • Regular exercise
In addition, patients should with comorbid conditions have their medications adjusted. Fenofibrate for hyperlipidemia and losartan should be preferred for hypertensive patients with hyperuricemia. Pharmacological intervention is not required in patients with asymptomatic hyperuricemia including those who have MSU (monosodium urate crystals) detected on imaging. Likewise, prophylactic treatment for urate stones is also not recommended. These patients may be advised adequate hydration and urinary alkalinization with potassium citrate or potassium bicarbonate.

Individuals with sustained marked hyperuricemia:

The target uric acid should be less than 6 mg/dl in patients with non-tophaceous gout and marked sustained hyperuricemia and a urate related medical condition that may result in obstructive uropathy or recurrent nephrolithiasis. In patients with marked asymptomatic hyperuricemia without a urate-related medical condition, the goal of treatment is less than 8 mg/dl.

Patients with marked asymptomatic hyperuricosuria:

Individuals with marked hyperuricosuria exceeding 1100 mg/dl per day should be initially treated with adequate hydration, urinary alkalinization (aim a urinary PH > 6.5), and protein restriction. The aim is to reduce the urinary uric acid excretion to less than 1000 mg/day. If the above interventions fail, allopurinol should be added aiming a serum uric acid of less than 6 mg.dl.

Patients with recurrent uric acid nephrolithiasis:

In patients with hyperuricemia and/or hyperuricosuria who have recurrent uric acid urolithiasis despite adequate hydration and alkalinization should be treated with allopurinol regardless of the baseline uric acid levels.

Tumor lysis syndrome:

Patients with a mitotic process who receive radiotherapy or chemotherapy and are at risk of developing acute urate nephropathy should be treated with allopurinol or febuxostat regardless of the baseline uric acid levels.

Asymptomatic hyperuricemia treatment in patients with medical conditions unassociated with crystal deposition:

Data regarding this subject is limited. Most experts recommend non-pharmacological interventions. However, in certain countries like Japan, asymptomatic hyperuricemia is treated with pharmacological intervention in patients who have hypertension or metabolic syndrome.

In conclusion:

Most patients with persistent asymptomatic hyperuricemia do not require pharmacological treatment. Initial management of asymptomatic hyperuricemia includes adequate hydration and a low protein diet. Patients with marked elevations in uric acid (greater than 10 mg/dl in women and greater than 13 mg/dl in men), history of recurrent urolithiasis, urate nephropathy or kidney disease, and risk factors like lymphoproliferative disorders should be treated with allopurinol or other agents.