Hyperuricemia

AUTHORS: Helen Zhang, BS and Manuel F. DaSilva, MD

Definition

Hyperuricemia is defined as high blood levels of uric acid based on physicochemical criteria. A statistical definition is inappropriate, as it would require certainty regarding the pathogenic cutoff or the plasma level above which monosodium urate (MSU) crystallizes. Plasma MSU is typically defined as 6.8 mg/dl but may differ depending on temperature and location in the body.¹ Serum uric acid >7.0 mg/dl in males or >6.0 mg/dl in females is generally indicative of hyperuricemia.² Some persons who are not hyperuricemic by this definition will have levels of uric acid that exceed the limit of solubility of uric acid in tissue. Age is an important risk factor in the increasing incidence of hyperuricemia and gout. Women become hyperuricemic at an older age than men due to the uricosuric effect of estrogen.³ Most people with hyperuricemia are asymptomatic and will remain so; however, 20% of those with serum uric acid >9 mg/dl will develop gout in 5 yr.⁴ Hyperuricemia is strongly associated with gout, obesity, diabetes, hypertension, and cardiovascular disease but has not been proven to cause any of these conditions.

Asymptomatic Hyperuricemia

Definition

Laboratory evidence of elevated serum uric acid without clinical disease known to be caused by hyperuricemia.

ICD-10CM CODE
E79.0		Hyperuricemia without signs of inflammatory arthritis and tophaceous disease

Etiology

Factors associated with urate variation are summarized in Table E1. Overproduction of uric acid accounts for a minority of cases of hyperuricemia. Most cases are a result of decreased renal clearance of uric acid and high dietary purine consumption. Fig. E1 describes factors affecting urate balance. Table E2 describes classification of hyperuricemia and gout.

Figure E1 Factors affecting urate balance.

The systemic urate pool and the likelihood of gout are determined by the dynamic balance among dietary purines, endogenous synthesis and recycling, and disposal by the kidney and gut. ATP, Adenosine triphosphate.

From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.

TABLE E1 Factors Associated With Urate Variation

Genetic Factors	Dietary Influences	Clinical Associations
Male sex Common variants associated with hyperuricemia (replicated) SLC2A9 ABCG2 PDZK1 GCKR RREB1 SLC17A3 SLC16A9 SLC22A11 SLC22A12 INHBC Rare monogenic causes HPRT deficiencies: Complete (Lesch-Nyhan syndrome), partial (Kelley-Seegmiller syndrome) PRPP synthetase overactivity Glucose-6-phosphatase deficiency Fructose-1-P aldolase deficiency Myogenic glycogenoses (types III, V, VII) Uromodulin-associated kidney disease: FJHN, MCKD types 1 and 2	Associated with increased urate High purine foods (e.g., red meat, liver, offal, shellfish) Fructose- and sugar-sweetened drinks Alcohol (beer and spirits) Associated with lower urate Low-fat dairy products Cherries Vitamin C Coffee	Older age Postmenopause in women Medical comorbidities Hemolytic disorders Hemopoietic malignancies; tumor lysis Lactic or ketoacidosis; hypoxemic states Lead nephropathy, chronic low-level exposure Preeclampsia Renal impairment Psoriasis Vasopressin-resistant diabetes insipidus Bartter and Gitelman syndromes Down syndrome Hypertriglyceridemia Hypertension Obesity Cardiovascular disease Medications associated with hyperuricemia Aspirin (low dose) Chemotherapeutic cytotoxics Diuretics Pyrazinamide Ethanol Levodopa Nicotinic acid Cyclosporine and tacrolimus Medications associated with reduced serum urate Losartan Fenofibrate Leflunomide Calcium channel blockers Atorvastatin Sevelamer

Genetic Factors

Dietary Influences

Clinical Associations

Male sex
Common variants associated with hyperuricemia (replicated)

SLC2A9
ABCG2
PDZK1
GCKR
RREB1
SLC17A3
SLC16A9
SLC22A11
SLC22A12
INHBC

Rare monogenic causes

HPRT deficiencies: Complete (Lesch-Nyhan syndrome), partial (Kelley-Seegmiller syndrome)
PRPP synthetase overactivity
Glucose-6-phosphatase deficiency
Fructose-1-P aldolase deficiency
Myogenic glycogenoses (types III, V, VII)
Uromodulin-associated kidney disease: FJHN, MCKD types 1 and 2

Associated with increased urate

High purine foods (e.g., red meat, liver, offal, shellfish)
Fructose- and sugar-sweetened drinks
Alcohol (beer and spirits)
Associated with lower urate
Low-fat dairy products
Cherries
Vitamin C
Coffee

Older age
Postmenopause in women
Medical comorbidities

Hemolytic disorders
Hemopoietic malignancies; tumor lysis
Lactic or ketoacidosis; hypoxemic states
Lead nephropathy, chronic low-level exposure
Preeclampsia
Renal impairment
Psoriasis
Vasopressin-resistant diabetes insipidus
Bartter and Gitelman syndromes
Down syndrome
Hypertriglyceridemia
Hypertension
Obesity
Cardiovascular disease
Medications associated with hyperuricemia
Aspirin (low dose)
Chemotherapeutic cytotoxics
Diuretics
Pyrazinamide
Ethanol
Levodopa
Nicotinic acid
Cyclosporine and tacrolimus
Medications associated with reduced serum urate
Losartan
Fenofibrate
Leflunomide
Calcium channel blockers
Atorvastatin
Sevelamer

FJHN, Familial juvenile hyperuricemic nephropathy; HPRT, hypoxanthine-guanine phosphoribosyltransferase; MCKD, medullary cystic kidney disease; PRPP, 5-phosphoribosyl 1-pyrophosphate.

From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

TABLE E2 Classification of Hyperuricemia and Gout

Impaired Uric Acid Excretion
Primary gout with decreased uric acid clearance
Secondary gout
Clinical conditions
Reduced glomerular filtration rate
Hypertension
Obesity
Systemic acidosis
Familial juvenile hyperuricemic nephropathy
Medullary cystic kidney disease
Lead nephropathy
Drugs
Diuretics
Ethanol
Low-dose salicylates (0.3-3.0 g/day)
Cyclosporine
Tacrolimus
Levodopa
Excessive urate production
Primary metabolic disorders
HPRT deficiency
PRPP synthetase overactivity
Glucose-6-phosphatase deficiency
Fructose-1-phosphate aldolase deficiency
Secondary causes
Clinical conditions
Myelo- and lymphoproliferative disorders
Obesity
Psoriasis
Glycogenoses III, V, VII
Drugs and dietary components
Nicotinic acid
Pancreatic extract
Cytotoxic drugs
Red meat, organ meat, shellfish
Alcoholic beverages (especially beer)
Fructose

HPRT, Hypoxanthine-guanine phosphoribosyltransferase; PRPP, phosphoribosyl pyrophosphate.

From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

Diagnosis ⬆ ⬇

Evaluation

The finding of hyperuricemia should prompt a thorough evaluation of potential causes and related diseases. Fig. E2 describes the evaluation of patients with hyperuricemia. If there is no clinical evidence of gout, nephrolithiasis, or acute kidney injury, the patient may be said to have asymptomatic hyperuricemia. Potential causes of elevated uric acid include malignancy, renal insufficiency, toxins, lead toxicity, drug side effect, or dietary indiscretion. If a careful history and physical exam do not reveal an evident cause of persistent hyperuricemia, a 24-h urine collection for uric acid and creatinine may be considered. Patients with urinary excretion of uric acid >800 mg/24 h are likely to be overproducers of uric acid and should be investigated more thoroughly for the underlying cause of their hyperuricemia.⁵

Figure E2 Evaluation of patients with hyperuricemia.

From Harris ED et al [eds]: Kelley’s textbook of rheumatology, ed 7, Philadelphia, 2005, Saunders.

Laboratory Tests

CBC with differential
CMP (blood urea nitrogen [BUN]/creatinine)
Urinalysis
Lipid profile
Consider 24-h urine collection for uric acid

Treatment ⬆ ⬇

No specific therapy is indicated for most patients with asymptomatic hyperuricemia. Lifestyle and dietary modification are often advisable.⁶

Nonpharmacologic Therapy

Weight loss, regular exercise
Reduce alcohol intake, especially beer
Reduce consumption of foods known to be high in purines such as red meat, organ meat, and high-fructose soft drinks

Pearls & Considerations ⬆ ⬇

Research from animal models and epidemiologic studies suggest there may be a causal relationship between hyperuricemia and early hypertension, but Mendelian randomization studies do not support this hypothesis.
Drugs that can be used to decrease hyperuricemia for an alternative condition should be considered. For example, in hypertension, the use of losartan or CCB and avoidance of diuretics if possible is preferred.
Patients with hyperuricemia and a family history of gout should be followed closely for the development of gouty arthritis.
Hyperuricemia in patients with gout should almost always be treated with urate-lowering medication (see “Gout”). The presence of gouty tophi or arthritis due to gout is generally an absolute indication for urate-lowering therapy.

There is evidence from several sources suggesting that treatment of hyperuricemia slows progression of chronic kidney disease (CKD) in patients without gout.⁷ However, one large randomized controlled study of febuxostat therapy in stage 3 CKD conducted in Japan was unable to replicate this finding.⁸ Current recommendations do not support the use of urate-lowering therapy in CKD unless there is concomitant gout, but the issue needs further study.

Recent studies have suggested that allopurinol use is associated with a reduced risk of myocardial infarction and reduction in all-cause mortality.⁹ These preliminary studies have sparked renewed research interest.

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Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

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