Last Updated on March 16, 2025
Gout is a type of crystal-induced arthropathy caused by the deposition of uric acid crystals. It is most often associated with high levels of uric acid called hyperuricemia. Another example of crystal-induced arthropathy is pseudogout.
Uric acid is a breakdown product of purines which are natural substances found in all of the body’s cells, and in all foods that we eat. An abnormality of metabolism of purines can lead to high levels of uric acid.
Gout occurs when uric acid crystallizes and deposits in joints leading to painful arthritis.
The gout crystals are monosodium urate monohydrate crystals.
There is no particular level of uric acid in the blood which could cause gout but most often triggered by changes in the level.
Thus while all persons with gout have hyperuricemia, all hyperuricemic persons may not have gout.
Males are more affected by gout as estrogens, the female hormones, have a mild uricosuric effect.
The rate of gout increases in the older population.
What are Risk Factors For Gout?
Following risk factors increase the chances of getting gout
- Obesity
- Moderate to heavy alcohol intake
- High blood pressure
- Abnormal kidney function
- Drugs that elevate levels of uric acid.
- Low levels of thyroid hormones
- Diabetes mellitus
- Hyperlipidemia
- Anemia
Cause of Gout
Gout may be either primary or secondary.
Primary Gout
Primary gout is said to be present when there is intrinsic [without any external cause]
- Underexcretion of uric acid
- Overproduction of uric acid
Uric acid is an end-stage by-product of purine metabolism. Uric acid is removed by excretion through kidneys. If the excretion is not sufficient to maintain serum urate levels below the saturation level [6.8 mg/dL], it is hyperuricemia and can lead to crystallization and deposit in soft tissues.
90% of patients of develop primary gout because of underexcretion.
The rest of the patients have it because of overproduction endogenously or consuming a lot of purines in the diet. Impaired intestinal elimination of uric acid, dietary excesses or alcohol overuse, and metabolic syndrome can affect the levels of uric acid.
Following genetic disorders are associated with overproduction of uric acid
- Glucose-6-phosphatase deficiency(von Gierke disease)
- Fructose 1-phosphate aldolase deficiency
- Hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome)
- Superactivity of phosphoribosylpyrophosphate synthetase
Secondary gout
It is caused by a secondary process or factor that causes an increase in the blood levels of uric acid.
Overproduction of uric acid
- High cell turnover conditions
- Myeloproliferative disorders
- Lymphoproliferative disorders
- Psoriasis
- Hemolytic anemias.
- Chemotherapy
- Obesity
- Excessive exercise
- Diet
- Foods that are rich in purines like anchovies, sardines, liver meat extracts etc
- Foods rich in fructose
Underexcretion of uric acid
- Renal disease
- Lead Nephropathy
- Starvation/ dehydration
- Drugs
- Loop and thiazide diuretics
- Niacin
- Low-dose aspirin
- Pyrazinamide
- Pembrolizumab
- Cyclosporine*- causes gout that can present after only a few years of hyperuricemia
Pathophysiology of Gout
A higher level of uric acid in the blood causes uric acid or urate to accumulate in blood and tissues. Saturation of the tissues with the deposits leads to precipitation of the urate salts, causing crystal formation.
The crystals are less soluble under acid conditions and at low temperatures, such as in cool, peripheral joints. Gout, therefore, affects cool peripheral joints like the metatarsophalangeal joint of the big toe early.
The uric acid levels are elevated for 10-20 years before the onset of gout.
The age of onset differs in men and women. The peak age of onset is the fourth to the sixth decade of life as uric acid levels start rising after puberty. In the case of a genetic disposition, the onset may occur even in the twenties.
As estrogens are uricosuric, the uric acid levels rise after menopause, and the peak age of onset in between 50-70 years.
The presence of urate crystals could remain asymptomatic until the interaction of naked urate crystals with receptors of local dendritic cells and macrophages triggers an immune reaction.
The naked urate crystals could be released due to
- Partial dissolution of a microtophus caused by changing serum urate levels
- Precipitation of crystals in a supersaturated microenvironment
The attack lasts for 3-10 days and subsides when damaged neutrophils are cleared and there is a production of anti-inflammatory cytokines. The change in the properties of urate crystals is another reason.
What is Tophi?
These are the collection of urate crystals in the soft tissues. Tophi may develop after about 10 years of untreated gout.
In women receiving diuretics, tophi may develop earlier.
Tophi are found in
- Along the helix of the ear
- Fingers
- Toes
- Prepatellar bursa
- Along olecranon
Tophi may ulcerate with trauma and ooze creamy discharge.
Associated Conditions
- Renal stones, colic and hematuria
- Sones may precede the onset of gout in 14%
- The majority of stones are uric acid, others could be calcium oxalate or calcium phosphate stones.
- Metabolic syndrome
- Insulin resistance/ diabetes
- Hypertension
- Hypertriglyceridemia
- Low levels of HDL
- Coronary artery disease, esp in metabolic syndrome patients
- Anterior uveitis due to deposition of intraocular urate crystals
Stages or Types of Gout
Asymptomatic hyperuricemia
- Elevated uric acid levels without any outward symptoms
- Lasts about 10-20 years before a gout attack occurs.
- Urate crystals are bein deposited
Acute gout or Flare
- Deposited urate crystals cause acute inflammation and intense pain.
- Lasts within 3 to 10 days
- Triggered by gout triggers – stressful events, alcohol, drugs, as well as cold weather etc.
Interval gout
- Also called intercritical gout
- The period in between two attacks of acute gout.
- Lasts from months to years
- Further urate crystal deposition in the tissues continue
Chronic tophaceous gout
- Chronic arthritis and damage to kidneys
- Presence of tophi or large lumps of urate crystals
What Causes Acute Attacks- The Gout Triggers?
The trigger for gout flares are triggered by acute increases or decreases in urate levels of the blood. This may lead to the formation, exposure, or shedding of crystals.
The following are the known gout triggers
- Acute alcohol intake
- Consumption of high-purine foods
- Rapid weight loss
- Trauma
- Dehydration
- Medications raising or lowering the uric acid levels.
Clinical History
Acute attacks are characterized by sudden excruciating pain and swelling of the joint. The great toe is the most common initially involved joint and and is eventually involved in 90% of cases. Other common sites are the ankle, wrist, finger joints, and knee.
Usually, one or two joints are involved but multiple joints can be involved either simultaneously or in rapid succession. Elderly women, particularly women on thiazide diuretics are known to have multiple joint involvement.
The attack is most intense at 3-10 hours after onset and lasts about 10 days.
Over time, upper limb involvement becomes more common. Polyarticular gout commonly involves the small joints of the fingers and toes, as well as the knees.
On examination, the involved joint at the time of the flare shows redness, swelling, and a loss of motion. Fever may be present, especially in polyarticular cases. [The features are similar to septic arthritis and should be ruled out]
The skin may desquamate [lose top layer] as the attack subsides.
Apart from an examination of the flared joints, other joints should be examined to look for signs of inflammation. The patient may be examined to look for tophi.
In chronic gout, the patients have chronic arthritis of the involved joints. This stage is seen in long-standing untreated gout and is uncommon.
The patient should be evaluated for the presence of risk factors for gout development and flaring.
Evaluation for associated conditions may be sought.
Differential Diagnoses
- Bursitis
- Pseudogout
- Psoriatic arthropathy
- Reactive arthritis
- Rheumatoid arthritis
- Cellulitis
- Septic Arthritis
Lab Studies
Synovial Fluid Analysis
Fluid is withdrawn from the joint via arthrocentesis and synovial fluid analysis is done. The most reliable test for gout is the presence of urate crystals in the synovial fluid or soft tissues. The usual findings are
- Cell count
- WBC often 10,000-70,000/µL
- Predominantly neutrophils
- Gram stain to rule out bacterial infection
- Culture and sensitivity
- Glucose levels- normal l [decreased in septic and rheumatoid arthritis]
- Microscopic analysis for crystals
- Found in 85% of cases
- Maybe negative in the early part of the flare
- Needle-shaped extracellular monosodium urate crystals
- Exhibit negative birefringence
Blood culture
Blood culture is done if septic arthritis is present with systemic signs.
Serum uric acid levels
-
- Increased levels seen in 95%
- An elevated level does not mean gout
- A normal level does not exclude the diagnosis.
Renal uric acid excretion [24-hour urinary excretion of uric acid]
- Indicated in high-risk patients
- Renal calculi
- A strong family history of gout
- First attack before age 25 years.
- Helps differentiate between overproduction and underexcretion of uric acid
Renal Function Test
- In patients with >1100 mg uric acid in 24 hours of urine. They have increased risk of renal stones and nephropathy.
in addition, other tests like blood sugar, lipid profiles, CBC, and ESR should be done to look for other associated findings
Imaging
X-rays
The X-rays may be normal in the initial part of the disease. Joint effusion is the earliest sign. The joint space is preserved until the late stages of the disease.
The presence of tophi is pathognomonic. They could be visible as shadows or as calcified lesions when calcified.
The typical finding in gouty arthritis is “punched-out” erosions with sclerotic margins with overhanging edges, also called as rat bite erosions. These findings are in a marginal and juxta-articular distribution.
Periarticular soft tissue swelling occurs due to the deposition of the tophi around the joint.
Ultrasound
Ultrasound may show urate crystal deposition in tissues of asymptomatic patients with hyperuricemia.
CT and MRI
CT and MRI are not used routinely. CT provides better details of x-ray findings.
Gadolinium-enhanced MRI helps to differentiate osteomyelitis.
Treatment
Asymptomatic hyperuricemia should not be treated, but patients with levels higher than 11 mg/dL are at risk for renal stones and renal impairment and need monitoring of renal functions.
Surgical tophi removal may be done if they are located in critical places or cause complications like deformity, infection, and compression effects.
Tophi with unrelenting pain or those that drain chronically could also be removed.
The treatment goals are as follows:
- Bring and keep serum uric acid levels below 6 mg/dL
- Reduction of the number of tophi
- Reducing pain and preventing further attacks.
Treatment of Acute Attacks
During acute attacks, the treatment aims to reduce pain and inflammation.
Drugs to control hyperuricemia are contraindicated in acute attacks [unless the heavy load puts kidneys at risk] because they can make the attack severe or prolong it even.
However, a patient already on the drugs at the time of the attack should continue those.
Following drugs are used in acute attacks
- Nonsteroidal anti-inflammatory drugs [Ibuprofen, Diclofenac etc]
- Drugs of choice
- Given for 2-5 days in maximum dosage
- The dose reduced and tapered over 2 weeks
- should be avoided in those with renal insufficiency, GI bleeding etc
- Colchicine
- Alternative to NSAIDs
- Less commonly used because of toxicity
- Dosage reduced in renal insufficiency and hepatic dysfunction.
- Corticosteroids
- When both the above drugs cannot be used
- Oral, or parenteral
- Intraarticular steroids can be used
- Tapered over 2 weeks
- ACTH (administration induces production corticosteroid by the patient’s own adrenal glands and can be considered.
A combination of two drugs can be used.
Treatment of Chronic Gout
This aims at reduction of uric acid levels, avoidance of triggers of attack and dietary changes to decrease purines in the diet.
Reduction of Uric acid levels
Most of the patients are put on drugs to lower serum uric acid levels after the first attack of gout. Some physicians recommend waiting for the second attack if the first one is not severe because not all patients experience a second attack.
Other measures are
- Stop contributing drugs if any
- Address predisposing medical conditions
- Stop alcohol intake
- Avoid purine rich foods
Urate-lowering drugs are recommended in patients who have >9mg/dL of serum uric acid levels [a higher risk for recurrent gouty arthritis and tophi].
American College of Rheumatology recommends urate-lowering therapy for patients with gout who have
- One or more tophi
- 2 or more attacks per year
Urate Lowering Drugs
The goal of therapy is to reduce serum uric acid levels to below 6 mg/dL.
Drugs used for lowering serum uric acid levels are
- Allopurinol
- Blocks xanthine oxidase and reduces the generation of uric acid.
- Febuxostat
- Selective inhibitor of xanthine oxidase
- Probenecid
- Increases excretion of uric acid
- Particularly indicated in underexcretors [<800 mg of uric acid in 24 hours]
- Contraindicated in renal stones or renal insufficiency
- Lesinurad
- Selective uric acid reabsorption inhibitor (SURI)
- Must be coadministered with a xanthine oxidase inhibitor
- indicated when the above drug is not completely effective
- Uricase
- Nonrecombinant urate-oxidase
- For prevention of severe hyperuricemia induced by chemotherapy in malignancy
- Polyethylene-glycol–conjugated uricase
- Enzymatically catalyzes the oxidation of uric acid to allantoin
- Can be considered along when other drugs are not able to control
Urate-lowering therapy can precipitate acute attacks of gout because of changes in levels of uric acid.
Therefore, colchicine or NSAIDs are added to the treatment for prophylaxis. Steroid, like prednisone, is another option.
In case the attack occurs after the commencement of the drug, the drug is to be continued while the flare is managed. [to avoid other shifts in levels and prolongation of the attack]
Diet and Lifestyle Changes
- Avoid purine-rich foods
- Avoid alcohol, sodas, and sweetened food
- Maintaining hydration with water
- Dehydration precipitates crystals
- A low-cholesterol to help prevent atherosclerosis.
- Weight reduction
It must be remembered that diet modification alone is not sufficient to lower uric acid levels so that tissue deposition is prevented.
The main aim of the restrictions is to reduce the triggers for flare.
Complications
- Severe degenerative arthritis
- Secondary infections
- Urate nephropathy
- Kidney stones
- Nerve or spinal cord impingement
- Fractures in joints with tophaceous gout
How To Prevent Gout Attacks?
One can take the following measures to reduce the chances of a gout attack.
- Drink plenty of fluids. This will aid in flushing out uric acid levels. Also decreases the chances of renal stones.
- Maintain good weight and avoid weight gain
- Avoid drinking – Alcohol is known to have diuretic effects that can contribute to dehydration and precipitate acute gout attacks. Alcohol can also affect uric acid metabolism and cause hyperuricemia.
- Avoid purine-rich foods. Foods rich in purines include shellfish and organ meats, such as liver, brains, and kidneys.
References
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Danve A, Sehra ST, Neogi T. Role of diet in hyperuricemia and gout. Best Pract Res Clin Rheumatol. 2021 Dec;35(4):101723. doi: 10.1016/j.berh.2021.101723. Epub 2021 Nov 19. [Link]
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Duskin-Bitan H, Cohen E, Goldberg E, Shochat T, Levi A, Garty M, et al. The degree of asymptomatic hyperuricemia and the risk of gout. A retrospective analysis of a large cohort. Clin Rheumatol. 2014 Apr. 33(4):549-53
- Richette P, Bardin T. Gout. Lancet. 2010 Jan 23. 375(9711):318-28.
- Singh JA, Reddy SG, Kundukulam J. Risk factors for gout and prevention: a systematic review of the literature. Curr Opin Rheumatol. 2011 Mar. 23(2):192-202.
- Sundy JS, Becker MA, Baraf HS, Barkhuizen A, Moreland LW, Huang W, et al. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum. 2008 Sep. 58(9):2882-91.
