Gout - Causes, Symptoms, Prevention and Treatment

Last Updated on July 31, 2019

Gout is a type of crystal-induced arthropathy caused by 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. If there is an abnormality of metabolism of purines, it leads to high levels of uric acid

Elevated serum uric acid levels are the main risk factor for developing gout. But the presence of hyperuricemia does not imply gout itself.

Gout occurs when uric acid crystallizes and deposits in joints leading to painful arthritis.

The gout crystals are monosodium urate monohydrate crystals.

The deposition of crystals could be without symptoms or can cause recurrent episodes of pain and joint inflammation.

Gout, if untreated, can lead to joint destruction and damage to kidneys.

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 but all hyperuricemic persons may not have gout.

Gout is found Worldwide and has varied prevalence in different countries. In the US its prevalence is about 4%.

Males are more affected by gout as estrogens, the female hormones, have a mild uricosuric effect.

The gout is often unusual in women who have not menopaused et.

The rate of gout increases in the older population. The gout is 5 times higher in persons in their seventies than who are younger than 50s.

Stages or Types of Gout

For gout attack to occur, there has to be hyperuricemia and urate crystal deposition. Following stages or types are known in the development of gout.

Asymptomatic hyperuricemia

This is the stage of hyperuricemia. The person may have elevated uric acid levels without any outward symptoms. Urate crystals are being deposited in tissue.

Lasts about 10-20 years before gout attack occurs.

Acute gout or Flare

Deposited urate crystals cause acute inflammation and intense pain.
Lasts within 3 to 10 days
Triggered by stressful events, alcohol, and drugs, as well as cold weather.

Interval gout

Also called intercritical gout
The period in between attacks of acute gout.
Lasts from months to years
Further urate crystals deposition in the tissues continue

Chronic tophaceous gout

Chronic arthritis and damage to kidneys
Presence of tophi or large lumps of urate crystals

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 occur in cool, peripheral joints. Gout, therefore, affects cool peripheral joints like 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 fourth to the sixth decade of life as uric acid levels start rising after puberty. In 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.

Presence of urate crystals could remain asymptomatic until the attack is triggered by the interaction of naked urate crystals with receptors of local dendritic cells and macrophages trigger 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.

Following conditions are associated with a higher incidence of gout

High blood pressure
Diabetes mellitus
Renal insufficiency
Hyperlipidemia
Obesity
Anemia

Associated Conditions

Renal colic and hematuria
- Due to high levels of uric acid
- Stones may precede the onset of gout in 14%
- 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

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 diuretic, 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

Cause of Gout

Gout may be either primary or secondary.

Primary Gout

Primary gout is said to be present when there us either underexcretion or overproduction of uric acid without any secondary reason for that.

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.

Rest of patients have it because of overproduction endogenously or consume 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.

medications of conditions that lead to an increase in blood levels of uric acid.

These conditions either lead to overproduction or undersecretion of uric acid.

Hig cell turnover causing the release of purines leads to overproduction and is seen in

Myeloproliferative disorders
Lymphoproliferative disorders
Psoriasis
Hemolytic anemias.

Increased cell death from chemotherapy also leads to increased purine levels and thus uric acid.

Obesity and excessive exercise are other causes.

Foods that are rich in purines also cause an increase of uric acid production. These foods include

Anchovies
Sardines
Sweetbreads
Kidney
Liver
Meat extracts

In addition to this, the consumption of foods rich in fructose is associated with an increased risk of gout.

Causes of secondary gout due to underexcretion of uric acid are

Renal disease
Lead Nephropathy (saturnine gout)
Starvation/ dehydration
Drugs
- Loop and thiazide diuretics
- Niacin
- Low-dose aspirin
- Pyrazinamide
- Pembrolizumab
- Cyclosporine*

*Cyclosporine causes an accelerated form of gout that can present after only a few years of hyperuricemia.

What Causes Acute Attacks of Gout?

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.

Following are the known triggers

Acute alcohol intake
Consumption of high purine foods
Rapid weight loss
Trauma
Dehydration
Medications raising or lowering the uric acid levels.

Complications of Gout

Severe degenerative arthritis
Secondary infections
Urate nephropathy
Kidney stones
Nerve or spinal cord impingement
Fractures in joints with tophaceous gout

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

Clinical History

The gout attacks are characterized by sudden excruciating pain and swelling of the joint.

The great toe is involved as the initial manifestation in 50% cases and is eventually involved in 90% 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 and eventually, multiple joint arthritis may occur. 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 flare show 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 as the attack subsides.

Apart from an examination of the flared joints, other joints should be examined to look for the 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

Lab Studies

Synovial Fluid Analysis

Most reliable test for gout is the presence of urate crystals in the synovial fluid or soft tissues

A newly occurring single joint arthritis should be subjected to arthrocentesis and synovial fluid analysis.

It is very important to rule out septic arthritis and treat promptly if present as it can cause joint damage very fast.

The joint fluid is investigated for

Cell count
- WBC often 10,000-70,000/µL
- Predominantly neutrophils
Gram stain to rule out bacterial infection
Culture and sensitivity
Microscopic analysis for crystals*
- Found in 85% of cases
- Maybe negative in the early part of the flare
- Extracellular monosodium urate crystals
- Needle-shaped
- Exhibit negative birefringence i.e. under the polarizing filter and red compensator filter
  - Yellow when aligned parallel to the slow axis of the red compensator
  - Turn blue when aligned across the direction of polarization
- Biochemical analysis
  - Normal glucose level [decreased in septic and rheumatoid arthritis]

*Crystals are water-soluble and dissolve in formalin, therefore best identified in tissue fixed with absolute alcohol–fixed tissue

Blood culture

Blood culture is done if septic arthritis is present with systemic signs. As septic arthritis can occur in presence of crystalline arthritis especially the old damaged joints.

Other Tests

Serum uric acid levels
- Hyperuricemia 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]
- 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
CBC
Elevated WBC count during attacks
ESR – usually elevated during acute attacks.
Serum Uric Acid
- Hyperuricemia not diagnostic
- 15% with gout may have normal levels
- Levels correlate with risk of developing gout
  - <7.9; 0.6% 5 yr risk
  - 8-8.9; 1%5 yr risk
  - >9; 22% if it is higher than 9 mg/dL.
Lipid profile – Following may be associated
- Increased triglycerides
- Decreased HDLs
Blood sugar levels [risk of developing diabetes present]
Renal Function Test
- In patients with >1100 mg uric acid in 24 hours urine
- Increased risk of renal stones and nephropathy.

Imaging

X-rays

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.

Joint effusion is the earliest sign. The x-rays may be normal in initial part of the disease. The joint space is preserved until late stages of the disease and there is no periarticular osteopenia.

Presence of tophi is pathognomonic. They could be visible as shadows or as calcified lesions when calcified.

Periarticular soft tissue swelling occurs due to 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 of Gout

The management of gout consists of treating the acute attacks, prevention of future flares by prophylaxis and tackling urate reserve by lowering stored and preventing further deposition.

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 which drain chronically could also be removed.

The treatment targets are as follows:

Bring and keep serum uric acid levels below 6 mg/dL
Reduction of 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 attack should continue those.

Following drugs are used in acute attacks

Nonsteroidal anti-inflammatory drugs
- Drugs of choice
- Given for 2-5 days in maximum dosage
- Dose reduced and tapered over 2 weeks
- Should be avoided in those with renal insufficiency, GI bleed 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

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 for lowering 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

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 change 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 shift in levels and prolongation of the attack]

Diet and Lifestyle Changes

Avoid purine rich foods [Read about purine-rich foods in detail]

- Organ meats [thymus, pancreas, liver, kidneys]
- Fish [sardines, smelt, anchovies, salmon, trout]
- Mussels
- Scallops
- Mutton
- Veal
- Liver
- Bacon
- Turkey
- 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.

Prognosis

Gout is associated with considerable morbidity, with acute episodes often causing incapacitation. However, gout that is treated early and properly carries an excellent prognosis

During the first 6-24 months of urate-lowering therapy, acute attacks of gout often occur more frequently.

Chronic injury to intra-articular cartilage leaves the joints more susceptible to subsequent joint infections.

It is reported that Risk for vascular disease is increased in patients with gout

How To Prevent Gout Attacks?

One can take the following measures to reduce the chances of the gout attack.

Drink plenty of fluids. This will aid in flushing out uric acid levels. Also decreases 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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Dalbeth N, Clark B, Gregory K, Gamble G, Sheehan T, Doyle A, et al. Mechanisms of bone erosion in gout: a quantitative analysis using plain radiography and computed tomography. Ann Rheum Dis. 2009 Aug. 68(8):1290-5.
Qaseem A, McLean RM, Starkey M, Forciea MA, Clinical Guidelines Committee of the American College of Physicians. Diagnosis of Acute Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016 Nov 1
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.

Gout – Causes, Symptoms, Prevention and Treatment