Uric acid plays multiple roles as danger signals during an innate immune response, maintaining electrolyte balance, and blood pressure regulation. This article elaborates on the various factors that are associated with hyperuricemia and the approach for managing uric acid levels.

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Uric acid metabolism

1. It depends on purine synthesis, purine salvage, purine degradation, uric acid excretion.
2. Uric acid production is via purine degradation in liver and intestinal cells.
3. Uric acid excretion is mainly by the kidney and partly by the G.I. tract.
4. Excretion involves filtration followed by reabsorption in proximal tubules and tubular secretion.
5. Around 80% of hyperuricemia is because of underexcretion.
6. Hyperuricemia can be:
   1. Asymptomatic hyperuricemia (majority)
   2. Symptomatic hyperuricemia - like gout, renal stones and uric acid nephropathy

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Multiple factors influencing uric acid level

1. Age: Uric acid increases with age. In females, hyperuricemia and related issues are seen in the postmenopausal age group because of the uricosuric effect of oestrogen.
2. Sex: Males have higher uric acid levels than females. Hyperuricemia is uncommon in premenopausal females, hence if seen, should think of any underlying genetic condition or underlying secondary condition causing hyperuricemia.
3. Genetics
   1. Overproduction:
      1. Gene mutation of the enzyme involved in purine synthesis- A gain of function mutation of PRPP (phosphoribosyl pyrophosphate) → purine synthesis → increased metabolite.
      2. Gene mutation of the enzyme involved in purine salvage- Loss of function of HGPRT (hypoxanthine-guanine phosphoribosyltransferase) - decreased purine salvage → increased degradation → end product uric acid.
         1. Complete deficiency- Leisch Nyhan syndrome
         2. Partial deficiency- Kelley Seegmiller syndrome
   2. Undersecretion: Gene mutation of protein URAT1 and organic anion transporters(OATs) in the Kidney and ABCG2 is involved in the excretion of uric acid.

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Drugs responsible for hyperuricemia 

• Diuretics- Thiazides and furosemide
• Antitubercular drugs- Pyrazinamide, ethambutol
• Nicotinamide
• Low dose salicylates
• Calcineurin inhibitors- Cyclosporine, tacrolimus
• Colony-stimulating factors
• Chemotherapy related

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Systemic conditions associated with hyperuricemia

• Psoriasis
• Metabolic syndrome
• Dyslipidemia, especially hypertriglyceridemia
• Cardiovascular disease
• Hypertensive disease of pregnancy like pre-eclampsia and eclampsia
• Sarcoidosis
• Obesity
• Bening haematological conditions like - Sickle cell disease, autoimmune hemolytic anaemia
• Myeloproliferative disorders
• Plasma cell dyscrasias
• Lymphoma and leukaemia
• GI malignancies

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Conditions associated with underexcretion

• Acute and chronic kidney disease
• Dehydration
• Hypovolemia

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Dietary factors associated with hyperuricemia (diet rich in purines and fructose)

• Sea food
• Red meat
• Alcohol and alcoholic beverages (e.g. beer)
• Food and drinks with high fructose corn syrup

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Approach to a patient with hyperuricemia

Around 80 to 90% have asymptomatic hyperuricemia.

Clinical history:

• Recurrent episodes of joint pain and swelling involving 1st MTP joint, midfoot, ankle, knee, wrist
• Usually, gout attacks are recurrent, episodic, monoarticular, severe, rapid progression within 24 hours, gross signs of inflammation, begin at night and spontaneous resolution
• The interictal period will be asymptomatic
• Chronic diseases can have tophi and polyarticular involvement
• History of renal colic, incidental finding of renal stones or recurrent bilateral nephrolithiasis
• Symptoms of kidney disease- Uremic or acidotic symptoms
• History suggestive of cardiovascular disease
• History of constitutional symptoms- Fever, weight loss, night sweats etc. (malignancies)
• History of chronic systemic diseases
• Drug history
• Diet history
• Alcohol history

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Laboratory and radiographic assessment

1. Complete hemogram with peripheral smear, renal and liver function test, serum uric acid level, urine examination.
2. Serum uric acid levels can be 40% times normal during acute attacks due to the uricosuric effects of cytokines. Hence it is recommended to assess uric acid level 4 weeks after the attack.
3. 24-hour urinary uric acid level to assess overproduction or underexcretion.

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Radiological assessment

1. Gout arthritis-related changes 
   1. Conventional radiography - acute episode - no changes, chronic tophaceous gout can have punched out erosions and sclerotic margins.
   2. Musculoskeletal ultrasonography of various joints - demonstrates gouty arthritis: "double contour sign" - suggestive of deposition of MSU crystals in articular cartilage.
   3. DECT (dual-energy CT) scan - demonstrates uric acid crystals in joints.
2. Ultrasound abdomen and pelvis- Preliminary test to see evidence of nephrolithiasis, kidney disease, organomegaly, any evidence of malignancy.
3. Chest x-ray PA view- Preliminary test; to look for any mediastinal lymphoma, sarcoidosis, chronic pulmonary disease, malignancies etc.

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When does hyperuricemia require treatment?

1. Asymptomatic hyperuricemia without any underlying cause requires no treatment.
2. If hyperuricemia is related to some underlying systemic or malignant condition - Hypouricemic agents might be required along with treatment of the systemic or malignant condition.
3. If hyperuricemia is related to drugs- switch drugs if possible, otherwise, add hypouricemic drugs to prevent hyperuricemia related adverse outcomes.
4. If a patient had uric acid-related nephropathy or nephrolithiasis - A hypouricemic agent might be required for the long term for uric acid-related stones.
5. Recurrent gout arthritis attack (2 or more per year).
6. Tophaceous gout and polyarticular gout.
7. Patient with gouty arthritis having radiographic evidence of damage.

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How to start hypouricemic agents?

1. There is always a risk of arthritis flare on the sudden change in serum uric acid level. Hence it is recommended to give hypouricemic agents along with prophylactic (colchicine, NSAIDs, glucocorticoids).
2. Hypouricemic agents should always be started four weeks after the acute attack and should be given along with prophylactic agents to prevent flare.

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What is the target of uric acid to be maintained?

Target serum uric acid to be maintained is less than 6 mg/dl.

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Till when do prophylactic agents need to be continued?

It is recommended to continue prophylactic agents 3 to 6 months after commencement of hypouricemic agent and achieve a target of less than 6mg/dl.

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What are uric acid lowering agents?

There are two main kinds of uric acid lowering agents- hypouricemic agents and uricosuric agents.

1. Hypouricemic agents reduce the production of uric acid by inhibiting enzyme xanthine oxidase - e.g. allopurinol and febuxostat, or metabolising end products e.g. rasburicase and pegloticase.
2. Uricosuric agents act by increasing uric acid excretion like probenecid. Allopurinol is the first-line agent recommended to start if there is no contraindication.

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What is the drug given for acute gout attack?

As per severity, a short course of low dose colchicine or NSAIDs or glucocorticoid as monotherapy or combination therapy is prescribed. Hyperuricemia is very common; 80-90% of it is asymptomatic which does not need treatment. It can be a marker of an underlying systemic condition or malignant disease which needs evaluation of the cause of hyperuricemia.

If hyperuricemia is symptomatic in terms of recurrent arthritis flare, associated with renal stone or associated with any underlying systemic conditions or secondary to the important drug should always be treated with uric acid.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a practising Rheumatologist from Bangalore.