Diet, including holiday-related overindulgence in shellfish, red meat, organ meat, processed foods like chips, and refined carbohydrates, especially those containing fructose.

alcohol use

Factors provoking acute attacks

 

●Circumstances that promote attacks of acute gouty arthritis include conditions that may provoke generalized disturbances in extracellular fluid urate concentrations or may increase the proinflammatory activities of cells interacting with monosodium urate (MSU) crystals deposited in tissues or in extracellular fluids [28].

These include trauma, surgery, starvation, fatty foods and other dietary overindulgence, dehydration, and ingestion of drugs affecting (raising or lowering) serum urate concentrations (eg, allopurinol, uricosuric agents, thiazide or loop diuretics, and low-dose aspirin). In men, increasing alcohol consumption (beer, spirits, and wine [29]) is associated with a proportionately greater risk of developing gout [30].

●High levels of meat and seafood consumption are associated with higher serum urate concentrations, while increased intake of low-fat dairy products correlates with lower urate levels [31]. The amounts of meat and seafood in the diet are significantly associated with an increased risk of developing gouty arthritis. This was illustrated in a prospective study of 47,150 male health professionals [32]. Those in the highest quintile of meat consumption had an adjusted hazard ratio (HR) of 1.41 compared with the lowest quintile; those consuming the largest amount of fish had an HR of 1.51. Neither the intake of purine-rich vegetables nor total protein intake was associated with an increased risk of gout.

By contrast, the highest quintile of dairy product consumption was associated with a nearly 50 percent reduction in risk compared with the lowest quintile [32]. In a separate report, higher coffee consumption was also associated with a lower risk of acute gout [33]. Consumption of coffee, but not tea, also reduced the risk of hyperuricemia, suggesting that the uric acid-lowering effect is not due to caffeine but to other components of coffee that are as yet unidentified [34].

 

●Local anatomic factors may predispose individual joints to gouty inflammation; these include locally elevated urate concentrations [35] in conjunction with repeated joint microtrauma, prior degenerative change, or reduced temperature in poorly perfused distal tissues [36].

 

Osteoarthritic changes in interphalangeal joints (Heberden's and Bouchard's nodes) may predispose these joints to develop coexisting gouty arthritis [25,37], particularly in older individuals with chronic kidney disease or in those receiving diuretic therapy. (See "Diuretic-induced hyperuricemia and gout".)

 

●The initiation of urate-lowering therapy, although protective in the long term, can precipitate acute gouty arthritis, particularly in the early months of urate-lowering treatment [38-42]. As a result, prophylaxis is usually given to prevent this complication [43]. (See "Prevention of recurrent gout: Pharmacologic urate-lowering therapy and treatment of tophi", section on 'Prophylaxis during initiation of antihyperuricemic therapy'.)

 

At least several of these factors are often present together and might work in combination. As an example, lower body temperature, relative dehydration, and relatively low blood cortisol levels are present during the overnight and early morning hours during which acute attacks are most likely to develop [44].

 

 

Gout is caused by the deposition of monosodium urate monohydrate crystals in the joints; the crystals can be seen with polarizing microscopy.

 

Etiology

The critical initiating factor in gout is the precipitation of monosodium urate crystals in synovial joints. This occurs when body fluids become supersaturated with uric acid (generally at serum levels >7 mg/dL). Indeed, the degree of hyperuricemia correlates well with the development of gout, with annual incidence rates of about 5% for serum uric acid levels more than 9 mg/dL. Increased levels of serum uric acid result either from underexcretion (90% of patients) or overproduction (10%) of uric acid.

A decreased glomerular filtration rate is the most frequent cause of decreased excretion of uric acid and may be due to numerous causes (see Chapter 16), but, regardless of etiology, impaired renal function is clearly related to the occurrence of gout. Diuretic administration is also a frequent cause of decreased excretion of uric acid. Overproduction defects can result from primary defects in the purine salvage pathway (eg, hypoxanthine phosphoribosyl transferase deficiency), leading to an increase in de novo purine synthesis and high flux through the purine breakdown pathway. Diseases causing increased cell turnover (eg, myeloproliferative disorders, psoriasis) and DNA degradation (eg, tumor lysis syndrome) are secondary causes of hyperuricemia.

Pathophysiology

Although the concentration of monosodium urate in joint fluid slowly equilibrates with that in the serum, formation of crystals is markedly influenced by physical factors such as temperature and blood flow. The propensity for gout to involve distal joints (eg, great toes and ankles), which are cooler than other body parts, probably reflects the presence of local physical conditions at these sites remote from the body core that favor crystal formation.

Monosodium urate crystals are not biologically inert. Their highly negatively charged surfaces function as efficient initiators of the acute inflammatory response. The crystals are potent activators of the classic complement pathway, generating complement cleavage products (eg, C3a, C5a) that are strong chemoattractants for neutrophil influx (Figure 24–2). The crystals also activate the kinin system and in that way induce local vasodilation, pain, and swelling. Phagocytosis of crystals by synovial macrophages activates the inflammasome (a complex of proteins that sense certain intracellular stressors and activate IL-1 maturation) and stimulates the release of proinflammatory cytokines (eg, IL-1, TNF, IL-8, PGE2). These products increase adhesion molecule expression on local vessel endothelium to facilitate neutrophil adhesion and migration and are also potent chemoattractants for neutrophils. Neutrophils also amplify their own recruitment by releasing leukotriene LTB4 upon phagocytosis of urate crystals (Figure 24–2).

 

X-Ray

Criteria

 

A decreased glomerular filtration rate is the most frequent cause of decreased excretion of uric acid and may be due to numerous causes but, regardless of etiology, impaired renal function is clearly related to the occurrence of gout. Diuretic administration is also a frequent cause of decreased excretion of uric acid. Overproduction defects can result from primary defects in the purine salvage pathway (eg, hypoxanthine phosphoribosyl transferase deficiency), leading to an increase in de novo purine synthesis and high flux through the purine breakdown pathway. Diseases causing increased cell turnover (eg, myeloproliferative disorders, psoriasis) and DNA degradation (eg, tumor lysis syndrome) are secondary causes of hyperuricemia.

Primary

Gout may be primary, due to overproduction or underexcretion of uric acid

Increased levels of serum uric acid result either from underexcretion (90% of patients) or overproduction (10%) of uric acid.

Secondary

Although gout is associated with hyperuricemia, gout attacks are not triggered by a particular level of uric acid; the typical trigger is acute changes in the level of uric acid, including a decrease in the concentration. All patients with gout have preexisting hyperuricemia; however, uric acid may be in the normal range at the time of an acute attack. Moreover, not all patients with hyperuricemia have gout. Hyperuricemia may also be found in patients administered diuretics, as well as in those taking niacin or low doses of aspirin.

Which of the following is a secondary cause of gout?

  1. Renal failure
  2. Lead poisoning
  3. Glycogen storage disease
  4. Myeloproliferative disease
  5. All of the above

 

 

 

{Genetic defect

Gout is a metabolic disorder in which uric acid, or urate, accumulates in the blood and tissues.

Deposition of monosodium urate crystals in the joint space leads to episodes of severe acute joint pain and swelling (particularly in the great toe, midfoot, ankle, and knee). These episodes tend to resolve completely and spontaneously within a week even in the absence of therapy. If not properly treated, however, this acute, self-limited form of the disease can evolve over many years into a chronic, destructive pattern resulting in more frequent and sustained periods of pain and resultant joint deformity. Accumulations of urate crystals elsewhere in the body can lead to subcutaneous deposits called tophi.

Uric acid induces inflammation of synovial joints. Tophi are collections of urate crystals in the soft tissues.

Tophi are classically located on the helix of the ear, but can occur in other locations (e.g., fingers, toes, prepatellar and olecranon bursae). Tophaceous gout leads to joint pain, swelling, and loss of range of motion.

Gout is characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage.

Uric acid renal calculi, tophi, and interstitial nephritis may also occur.

Adverse cardiovascular outcomes are becoming more clear as well. [elaborate]

Gout is usually associated with a high serum uric acid level (hyperuricemia), a poorly soluble substance that is the major end product of purine metabolism.

In most mammals, uricase converts uric acid to the more soluble allantoin; this enzyme is absent in humans.

While clinical gouty episodes are associated with hyperuricemia, most individuals with hyperuricemia may never develop a clinical event from urate crystal deposition.

 

 

 

 

Patients who are older or who have renal insufficiency or diabetes are at increased risk of gout because of decreased excretion of uric acid.

A yellowish substance may be seen under the skin or may be expressed from the tophi. Needle aspiration demonstrates negatively birefringent needle-shaped crystals using polarized light microscopy; culture results are negative. Radiography may demonstrate bony erosions with sclerotic borders, calcified tophi, and complete destruction of the joint with reabsorption of the phalangeal bones. Osteoarthritis is a chronic, degenerative disease that can involve the distal and proximal joints of the hand, and can be mono- or polyarticular.

Manifestations include stiffness, gelling, crepitus, and tenderness along the joint line. Bony enlargement, Heberden nodes, and Bouchard nodes are smaller than tophi. Needle aspiration demonstrates a noninflammatory cell count. Radiography shows joint space narrowing, subchondral sclerosis, and osteophytes.

Psoriatic arthritis is a chronic inflammatory arthritis that develops in up to 5% of patients with psoriasis. It is characterized by distal interphalangeal joint involvement and dactylitis with sausage digits.

Most patients with psoriatic arthritis have concurrent involvement of the skin and nails, and have human leukocyte antigen-B27. Radiography shows a pencil-in-cup deformity.

Rheumatoid arthritis is a chronic systemic inflammatory disease with persistent, symmetric polyarthritis (synovitis).

The proximal small joints of the hands and feet are often affected. There may be extra-articular involvement of the skin, heart, lungs, and eyes. Although rheumatoid nodules are occasionally mistaken for tophi, patients with rheumatoid arthritis have rheumatoid factor and anti-cyclic citrullinated peptide antibodies, multisystem disease, and symmetric joint involvement, and they lack the yellowish discoloration or discharge. Radiography shows erosions and joint space narrowing.

Septic arthritis is an acute joint infection manifesting as pain, erythema, and joint swelling. It can affect any joint

and is usually caused by Staphylococcus aureus infection. Patients often have fevers and other systemic symptoms. Needle aspiration demonstrates a high leukocyte count and typically positive culture findings. Radiography shows swelling without bony involvement.

 

It is a common condition, presenting in approximately 4% of the adult American population, and it is approximately 3 times more common in men than women.

 

Hyperuricemia and gout are often associated with one or more major disorders such as hypertension, obesity, diabetes, hyperlipidemia, atherosclerosis, and ethanol abuse. These issues and strategies to address them, such as changes in diet and careful attention to the impact on hyperuricemia and gout of medications used for the management of hypertension,

 

Acute Gout

Without therapy, acute gouty arthritis usually resolves completely within a few days to several weeks, particularly in early disease.

Symptoms improve more quickly with administration of any of a broad array of antiinflammatory drugs.1

Therapy for an acute gouty attack targets the proinflammatory mediators.

NSAIDs such as ibuprofen reduce prostaglandin synthesis,

Colchicine

Colchicine impairs the migration of neutrophils into the joints,

The recommended dosage of colchicine depends on the patient's age, renal function, hepatic function, and use of co-administered drugs

Prophylaxis of Gout Flares:
The recommended dosage of colchicine for prophylaxis of gout flares for adults and adolescents older than 16 years of age is 0.6 mg once or twice daily. The maximum recommended dose for prophylaxis of gout flares is 1.2 mg/day.

 

Treatment of Gout Flares:
The recommended dose of colchicine for treatment of a gout flare is 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. Higher doses have not been found to be more effective. The maximum recommended dose for treatment of gout flares is 1.8 mg over a 1 hour period.

Colchicine may be administered for treatment of a gout flare during prophylaxis at doses not to exceed 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. Wait 12 hours and then resume the prophylactic dose.

 

 

 

 

 

RENAL DOSING

dialysis Prophylaxis of Gout Flares:
For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine.

However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring

Treatment of Gout Flares:
For treatment of gout flares in patients with mild (Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every 2 weeks. For patients with gout flares requiring repeated courses consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (1 tablet). For these patients, the treatment course should not be repeated more than once every 2 weeks

Treatment of gout flares with Colchicine is not recommended in patients with renal impairment who are receiving Colchicine for prophylaxis.

Creatinine clearance for males = [140-age (years)]× [body wt (kg)]
72 × [serum creatinine (mg/dL)]
Creatinine clearance for females = [140-age (years)]× [body wt (kg)]× 0.85
72 × [serum creatinine (mg/dL)]

 

 

 

 

 

corticosteroids deactivate myelomonocytic cells responsible for crystal phagocytosis and subsequent cytokine release.

Treatment is offered to alleviate symptoms and reduce the duration of the flare.

On the other hand, uricosuric agents, such as probenecid, and xanthine oxidase inhibitors, such as allopurinol and febuxostat, and pegloticase, which converts uric acid to allantoin, an inactive and soluble metabolite that is readily excreted by the kidneys, are typically reserved for the prevention of future attacks.


Pathophysiologic events in a gouty joint. Synoviocytes phagocytose urate crystals and then secrete inflammatory mediators, which attract and activate polymorphonuclear leukocytes (PMN) and mononuclear phagocytes (MNP) (macrophages). Drugs active in gout inhibit crystal phagocytosis and polymorphonuclear leukocyte and macrophage release of inflammatory mediators. PG, prostaglandin; IL-1, interleukin-1; LTB4, leukotriene B4.

Image not available.

 

 

 

Hyperuricemia and gout are often associated with one or more major disorders such as hypertension, obesity, diabetes, hyperlipidemia (components of the metabolic or insulin resistance syndrome [5]), atherosclerosis, and ethanol abuse.

Risk Reduction

achievement of ideal body weight

limitation of ethanol consumption

In some patients, treatment of the accompanying disorder, particularly the use of diuretics to treat hypertension, may adversely affect gout (see 'Hypertension and diuretics' below). Low-dose aspirin, commonly used for cardiovascular risk reduction, may also increase the risk of acute gout (see 'Other drugs and diseases' below). Thus, preventive efforts, depending upon the comorbidities present, might include:

●Reduction to ideal body weight (see 'Weight loss' below)

●Changes in dietary intake and composition (see 'Dietary composition' below)

●Reduction of alcohol intake (see 'Alcohol' below)

●Dietary supplementation such as with vitamin C (see 'Other dietary supplements and vitamins' below)

●Substitution, where possible, for medications and/or dietary additives that reduce urate excretion or increase uric acid production (see 'Hypertension and diuretics' below)

●Management of comorbid diseases common in patients with gout, such as hypertension, chronic renal functional impairment, cardiovascular disease, and the components of the metabolic syndrome.

 

 

 

Therapy for acute gouty arthritis consists of agents that decrease inflammatory cell recruitment and activation to the involved joints.

Prevention or prophylaxis of recurrent attacks of gouty arthritis requires chronic therapy to decrease serum uric acid levels into the normal range, where dissolution of crystals is favored.

Several agents are available that can accomplish this purpose. These include uricosuric agents (eg,probenecid), which enhance excretion of uric acid into the urine, allopurinol and febuxostat, which impede uric acid synthesis by inhibition of xanthine oxidase (a critical enzyme in the uric acid synthetic pathway), and pegloticase, which converts uric acid to allantoin, an inactive and soluble metabolite that is readily excreted by the kidneys.

Conceptually, the xanthine oxidase inhibitors, allopurinol and febuxostat, are most appropriate for the treatment of uric acid overproduction (10% of patients), the uricosuric agent, probenecid, for the treatment of uric acid underexcretion (90% of patients), and pegloticase for the rare cases of refractory gout.

However, agents that decrease uric acid production can be used for therapy of hyperuricemia irrespective of cause and are often more convenient in terms of dosage regimens.

 

Content 4

Content 3

Content 11

A 58-year-old man with a long history of treated essential hypertension and mild renal insufficiency presents to the urgent care clinic complaining of pain in the right knee.

His primary care provider saw him one week ago and added a thiazide diuretic to improve his blood pressure control. He had been feeling well until the night before the clinic visit, when he noted some redness and slight swelling of his knee. He went to sleep and was awakened early by significant swelling and pain. He was able to walk only with assistance. He has no history of knee trauma.

Physical examination confirmed the presence of a swollen right knee, which was erythematous and warm. Joint aspiration recovered copious dark yellow, cloudy synovial fluid. Microscopic analysis demonstrated 30,000 leukocytes/μL, a negative Gram stain, and many needle-like, negatively birefringent crystals consistent with acute gout.

 

Content 2

Content 3

A 58-year-old man with a long history of treated essential hypertension and mild renal insufficiency presents to the urgent care clinic complaining of pain in the right knee. His primary care provider saw him one week ago and added a thiazide diuretic to improve his blood pressure control. He had been feeling well until the night before the clinic visit, when he noted some redness and slight swelling of his knee. He went to sleep and was awakened early by significant swelling and pain. He was able to walk only with assistance. He has no history of knee trauma.

Physical examination confirmed the presence of a swollen right knee, which was erythematous and warm. Joint aspiration recovered copious dark yellow, cloudy synovial fluid. Microscopic analysis demonstrated 30,000 leukocytes/μL, a negative Gram stain, and many needle-like, negatively birefringent crystals consistent with acute gout.

Questions

A. What factors may have precipitated this gout flare?

a. The mild renal insufficiency may be associated with a decreased glomerular filtration rate and thus poor urate excretion. b. High Blood pressure c.

C.

Answer

 

B. Describe the inflammatory pathways involved in acute gout.

Multiple inflammatory pathways are invoked by the negatively charged urate crystals. For example, they activate the classic complement pathway whose cleavage products serve as effective neutrophil chemoattractants. The kinin system is stimulated by crystals as well, contributing to the inflammatory signs seen on examination such as tenderness and erythema from local vasodilation. In addition, macrophages phagocytose urate crystals, initiating the release of proinflammatory cytokines (eg, IL-1 and TNF), which activate the vascular endothelium, encouraging neutrophil adhesion and migration. Neutrophils are able to simulate their own recruitment by releasing leukotriene B4 in response to urate crystal phagocytosis.

C. What agents should the urgent care physician consider in treating this gout flare? What are their mechanisms of action?

Therapy for an acute gouty attack should target the proinflammatory mediators described previously. NSAIDs such as ibuprofen reduce prostaglandin synthesis, colchicine impairs the migration of neutrophils into the joints, and corticosteroids deactivate myelomonocytic cells responsible for crystal phagocytosis and subsequent cytokine release. Because gouty flares are typically self-limited events, treatment is offered to alleviate symptoms and reduce the duration of the flare. On the other hand, uricosuric agents, such as probenecid, and xanthine oxidase inhibitors, such as allopurinol and febuxostat, and pegloticase, which converts uric acid to allantoin, an inactive and soluble metabolite that is readily excreted by the kidneys, are typically reserved for the prevention of future attacks.

 

When treating gout, which one of these drugs for gout will be ineffective in those with renal insufficiency?

The correct answer is "B."Probenecid is a uricosuric agent that is ineffective—and contraindicated—in renal insufficiency. Depending on the degree of renal insufficiency, indomethacin might also be contraindicated but it would still be effective.

 

A 42-year-old man presents to his family physician because of complaints of severe pain in the great toe of his left foot. Which of the following statements best explains this patient's condition?

The condition is not related to his obesity or alcohol use

Most likely he has some underlying condition that is causing him to produce an excessive amount of uric acid

This disease process will never cause him to lose renal function

Histologic analysis of the synovium would reveal needle-shaped, strongly negatively birefringent crystals

The correct answer is D.

The patient's clinical presentation is characteristic for gout. Alcohol use and obesity are risk factors for gout. Most patients are underexcretors of uric acid, and not overproducers. Gout can contribute to the development of uric acid stones in the kidney, and also to the precipitation of uric acid into the renal interstitium.

 

Which of the following antihypertensive medications should be avoided in patients with gout?

Losartan

Hydrochlorothiazide

Nifedipine

Atenolol

Answer

Answer: B

Thiazide diuretics such as hydrochlorothiazide and loop diuretics such as furosemide may increase blood uric acid levels, thereby increasing the risk of gouty flares. Calcium channel blockers (CCBs) and the angiotensin II receptor blocker (ARB) losartan may decrease the incidence of gouty flares. Beta blockers such as atenolol are not associated with increased risk of gout flares.

Reference: Hainer BL, Matheson E, Wilkes RT. Diagnosis, Treatment, and Prevention of Gout. Am Fam Physician. 2014;90(12):831-836. Pubmed ID: 25591183.

 

A 56-year-old man presents to the clinic due to recurrent attacks of severe pain in his right big toe for the last few weeks. During the attacks, his toe becomes painful, red, warm and swollen. Significant improvement occurs after treatment with colchicine. Synovial fluid analysis is performed to confirm the diagnosis.

What is the most likely finding to confirm the diagnosis?

A- Calcium oxalate crystals

B- Calcium pyrophosphate dehydrate crystals

C- Cholesterol crystals

D- Cloudy, reddish fluid, with leucocytes’ count equal to the blood count

E- Negatively birefringent urate crystals

Answer



This is a case of gout supported by the patient complaint of recurrent inflammation of the big toe and improvement of symptoms after the use of colchicine. Acute gout is confirmed by the detection of negatively birefringent monosodium urate crystals in synovial fluid analysis. Calcium pyrophosphate dehydrate crystals are found in cases of pseudo-gout. Acute arthritis is characterized by cloudy, bloody synovial fluid with leucocytes count equal to the blood count (normally synovial fluid may contain up to 200 cells /UL white blood cells). Cholesterol crystals are seen in patients with hypercholesterolemia and rheumatoid arthritis while calcium oxalate crystals can be seen in patient with renal diseases on dialysis.

The correct answer is E

 

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