Hyperuricemia is an elevated uric acid level in the blood. The normal upper limit is 6.8mg/dL, and anything over 7 mg/dL is considered saturated, and symptoms can occur.
This elevated level is the result of increased production, decreased excretion of uric acid, or a combination of both processes.
Elevated uric acid can also be seen in accelerated purine degradation, in high cell turnover states (hemolysis, rhabdomyolysis, and tumor lysis) and decreased excretion (renal insufficiency and metabolic acidosis). Hyperuricemia can lead to gout and nephrolithiasis. It has also been implicated as an indicator for diseases like metabolic syndrome, diabetes mellitus, cardiovascular disease, and chronic renal disease.
Purine rich diet
Error of purine metabolism: hypoxanthine phosphoribosyltransferase (HPRT) deficiency, phosphoribosylpyrophosphate (PRPP) synthetase over activity
Cell breakdown or turnover: lymphoproliferative diseases, myeloproliferative disease, polycythemia vera, Paget disease, psoriasis, tumor lysis, hemolysis, rhabdomyolysis, exercise
Decreased Uric acid Excretion
Acute or chronic kidney disease, acidosis (lactic acidosis, ketoacidosis), hypovolemia, medication/toxin (diuretic, niacin, pyrazinamide, ethambutol, cyclosporin, beryllium, salicylates, lead, alcohol), sarcoidosis, hyperparathyroidism, hypothyroidism, Bartter syndrome, Down syndrome
It is estimated as much as 21% of the general population and 25% of hospitalized patients have asymptomatic hyperuricemia. The most common complication of hyperuricemia is gout which is seen in 3.9% of the U.S. population. Hyperuricemia does not in itself indicate a pathological state because it is very prevalent in the general population.
Uric acid (2,6,8 trioxypurine-C5H4N4O3) is the result of purine breakdown. At the normal physiological pH of 7.4, uric acid circulates in the ionized form of urate. Purine metabolism mainly occurs in the liver, but it can also be produced in any other tissue that contains xanthine oxidase (intestines). About two-thirds of uric acid is excreted in the kidneys, and a third is excreted into the intestine. In the kidneys, it is filtered and secreted, and 90% is reabsorbed. Other mammals have lower uric acid levels due to the activity of uricase. This enzyme converts urate to the more water soluble form of allantoin.
Urate production is accelerated by purine rich diets, endogenous purine production, and high cell breakdown, and it is responsible for a minority of cases of hyperuricemia. Foods rich in purine include all meats but specifically organ meats (kidneys, liver, “sweet bread”), game meat,s and some seafood (anchovies, herring, scallops). Beer, which is purine rich, also increases uric acid levels by decreasing kidney excretion. Endogenous production of the purine production can be accelerated by phosphoribosylpyrophosphate (PRPP) synthetase activity as well as a defect in the regulatory enzyme hypoxanthine phosphoribosyltransferase (HPRT). Conditions of accelerated cell breakdown or turnover such as rhabdomyolysis, hemolysis, and tumor lysis can also be a purine source and thus, increase urate production.
Urate excretion occurs primarily in the kidneys and is responsible for hyperuricemia in 90% of individuals. Underexcretion appears to be a combination of decreased glomerular filtration, decreased tubular secretion, and enhanced tubular reabsorption. The acute or chronic decrease in glomerular filtration can result in hyperuricemia. Proximal tubular reabsorption of uric acid is controlled by URAT1 (uric acid transporter 1). This transported can be stimulated by organic acids (lactate and acetoacetate, and beta-hydroxybutyrate), medications (niacin, pyrazinamide, ethambutol, cyclosporin, and chemotherapy) and reduced extracellular fluid volume resulting in hyperuricemia.
Gout is a metabolic disorder that allows for the accumulation of uric acid in the blood and tissues. This leads to the precipitation of urate monohydrate crystals within a joint. When tissues are saturated with urate, crystals will precipitate. Precipitation is enhanced in acidic environments and cold environments, leading to increased precipitation in peripheral joints, such as the great toe. Gout has a male predominance in a 4:1 ratio of men to women. Uric acid levels can be elevated ten to 15 years before clinical manifestations of gout.
In uric acid nephrolithiasis, uric acid is handled by the renal system, and three factors can influence uric acid stone formation. These factors are TH acidic urine, dehydration, and hyperuricosuria. Persistent acidic urine is the most common cause of uric acid stone formation. Hyperuricosuria is defined as uric acid levels that exceed 800 mg/day in men and 750 mg/day in women. It is most commonly associated with increased dietary intake. Uric acid stones are 5% to 10% of all urinary stones.
Hyperuricemia does not represent a disease or a specific indication for therapy. The majority of patients with elevated uric acid are asymptomatic and require no long term therapy. The patient may give a history of a purine rich diet or alcohol consumption, specifically beer. Past medical history, as well as current medications, should be reviewed to find a correlation with poor renal excretion of urate or increased production.
The two most common complaints associated with hyperuricemia are gout and uric acid nephrolithiasis.
With gout, a patient will complain of red hot swollen joint, most commonly in the big toe.
With nephrolithiasis, patients will complain of flank pain, hematuria, nausea/vomiting, and colicky pain.
There will be no specific physical exam finding that will indicate hyperuricemia unless the patient is presenting with complaints of gout or nephrolithiasis.
With gout, there is evidence of an erythematous, warm, and swollen joint. Most commonly affects the big toe, but can affect any joint in the body. Usually, gout affects one joint at a time.
Nephrolithiasis has no specific physical exam findings but may have costovertebral angle tenderness. Look for hematuria on urinalysis.
Lab studies will most likely reveal the following:
Serum uric acid: normal is less than 6.8 mg/dL
Twenty-four--hour urine uric acid collection should be less than 600 mg/day for an adult male on a purine free diet. A level above this implies elevated uric acid production.
Consider complete blood count (CBC), CMP, lipid profile, calcium and phosphate levels. These laboratory studies are to assess for underlying disease leading to elevated uric acid but are adjunct studies.
Consider joint x-rays to evaluate joint swelling; however, x-rays are not necessary for the diagnosis of gout.
Renal ultrasounds are indicated in patients with uric acid nephrolithiasis.
Consider joint aspiration to evaluate for uric acid crystals, look for negatively birefringent under polarized microscopy.
Routine screening for hyperuricemia is not recommended.
The majority of patients are asymptomatic and do not need medical therapy for hyperuricemia as they will never develop gout or nephrolithiasis. The unnecessary cost of medication and potential for adverse effects outweighs the benefit of starting medication. Urate lowering medications in asymptomatic patients are only indicated in those undergoing cytolytic therapy for malignancy to prevent tumor lysis syndrome.