Gout: Types, Causes, Risk Factors, Symptoms, Treatment & Prevention
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| Gout Or Gouty Arthritis |
Gout
Gout is the most widely recognized inflammatory joint disease in men and the most well-known inflammatory arthritis in older women. It is unequivocally related to age.
Gout is a metabolic disorder that causes the inflammation of joints resulting in sudden and severe pain and swelling. It is a common type of arthritis.
It is brought about by the deposition of monosodium urate crystals in joints within articular and periarticular tissue and soft tissues following ongoing hyperuricemia. The level of elevation of uric acid levels over the immersion point for urate crystal formation is a significant determinant in accelerating an assault.
Persistent and chronic hyperuricemia is related to issues of purine metabolism due to under discharge or over the creation of uric acid, the last metabolite of endogenous and dietary purine metabolism.
The reference or normal value of uric acid in adult males is 4.0-8.5 mg/dL or 0.24-0.51 mmol/L. and in adult females is 2.7-7.3 mg/dL or 0.16-0.43 mmol/L.
Gout typically presents as a monoarthritis in the first metatarsophalangeal joint (large toe) of the foot and is regularly alluded to as podagra (from the Greek 'holding onto the foot'). The resulting assaults might be polyarticular.
Other generally influenced joints incorporate the midfoot, lower leg, knee, wrist, and finger joints. Albeit the assault is extremely painful, it is normally self-restricting, resolving unexpectedly in 1-14 days.
Acute gouty attacks are relieved on their own by taking proper rest, ice, and taking one of the accompanying pharmacological drugs such as NSAIDs, colchicine, or corticosteroids. A few patients may just at any point experience one attack yet frequently a subsequent attack happens within 6–12 months, with an expanded danger of resulting assaults. Patients with recurrent attacks require long-term prophylaxis with drugs that bring down the serum urate level.
Gout is one of the most perceived sicknesses and was distinguished by the Egyptians in 2460 BC. Hippocrates portrayed it as joint inflammation of the rich because of the relationship with specific food varieties furthermore, liquor.
Gout influences 1–2% of adult populations in developed nations, furthermore, ongoing a long time there has been a critical rise in its predominance and rate (Zhang et al., 2006). The USA has seen a multiplying in the number of cases with the pace of gout expanding to 4.1% in older males.
It is quite possibly the most well-known type of inflammatory joint illness in men more prominent than 40 years old. Men are more vulnerable to gout than ladies. Yet, ladies after menopause are likewise at higher danger of developing gout.
Individuals with hypertension, kidney illnesses, thyroid infection, diabetes, or sleep apnea are additionally at higher danger of developing gout. There is no remedy for gout except for you can successfully manage it with specific meds and way of life changes.
The best choice of medication is generally allopurinol, notwithstanding, a small percentage of patients can't endure allopurinol and require treatment with an option urate-lowering agents, for example, febuxostat or uricosuric agents, for example, benzbromarone, sulfinpyrazone, or probenecid.
It is fundamental that pharmacological measures are joined with non-pharmacological measures, for example, dietary and way of life change to forestall intermittent attacks. Inappropriate management of gout can result in ongoing tophaceous gout with polyarticular, dangerous poor quality joint aggravation, joint disfigurement, and tophi.
Types Of Gout
There are two main types of gout, primary or secondary depending upon the causative agents.
Primary Gout
Primary gout isn't an outcome of an acquired disorder yet is related to uncommon congenital errors of metabolism and segregated renal tubular defects in the partial clearance of uric acid.
Secondary Gout
Secondary gout develops as a consequence of the use of specific drugs or as a consequence of other disorders. Myeloproliferative and lymphoproliferative disorders, psoriasis, and hemolytic anemia, and can cause hyperuricemia. Renal mechanisms are responsible for the majority of hyperuricemia in individuals with overproduction representing less than 10% of patients with gout.
Drugs involved in causing gout are alcohol, aspirin, ciclosporin, cytotoxic chemotherapy, diuretics (both loops and thiazides), ethambutol, levodopa, pyrazinamide, ribavirin and interferon, and teriparatide.
Another classification of gout is based on the severity of symptoms and diseases. So, there are two types of gout depending upon the severity, acute gout, and chronic gout.
Acute Gout
Acute gout for the most part influences one or not many joints simultaneously. The lower leg, big toe, and ankle joints are primarily influenced. The attack of acute gout may disappear within a couple of days. It can get back every once in a while.
Chronic Gout
The frequency of attacks and severity of symptoms increases in chronic gout. In chronic gout, the deposition of uric acid occurs in the eyelids, nose, and pinna of the external ear and around major joints which is known as tophi.
Causes Of Gout
Gout is caused by increased uric acid production in the body or decreased uric acid excretion from the body. This results in the accumulation of monosodium urate crystals in the joints and soft tissues of the body.
When the breakdown of cellular nucleoproteins and purine nucleotides occurs, uric acid is mainly a by-product of this breakdown. It is a weak acid with a pKa of 5.75, and at the physiological pH of the extra-cell compartment, 98% of uric acid is in the ionized type of urate.
This is fundamentally present as monosodium urate because of the great concentration of sodium in the extracellular compartment. Human beings and higher primates lack the enzyme uricase. Uricase is involved in the breakdown of uric acid to the exceptionally dissolvable allantoin bringing about higher centralizations of urate near the degree of solubility.
Monosodium urate has a dissolvability limit of 380 μmol/L when the fixation surpasses 380 μmol/L, there is a danger of precipitation and the arrangement of monosodium urate crystals.
The urate production is subject to the harmony between purine ingestion, de novo synthesis in the cells, and the activities of xanthine oxidase at the distal end of the purine pathway. Xanthine oxidase is the protein that catalyzes the oxidation of hypoxanthine, the breakdown item from the catabolism of cell nucleoproteins and purine nucleotides, to xanthine and xanthine to uric acid. This causes the onset of pain, redness, heat, and swelling in the joints.
Risk Factors Of Gout
Genetics, renal disease, comorbidities for example obesity, dyslipidemia, glucose intolerance, hypertension, diet, alcohol consumption, and certain medication are the major risk factors for gout.
A polymorphism of the SLC22A12 gene which encodes for URAT-1 has been associated with underexcretion of uric acid and hyperuricemia. However, the exact role of genetics is not fully understood.
Certain drugs such as alcohol, aspirin, ciclosporin, cytotoxic chemotherapy, diuretics (both loops and thiazides), ethambutol, levodopa, pyrazinamide, ribavirin, and interferon increase the risk of gout.
The risk of gout is higher in people who consume large quantities of red meat. Increased daily consumption of alcohol is associated with a higher risk of gout.
Symptoms Of Gout
People diagnosed with gout may develop the symptoms of joint pain, joint inflammation and swelling, warmth joint, joint redness, and joint tenderness. The pain reported in gout is throbbing, crushing, or excruciating in nature. Fever is rarely reported along with these symptoms.
In the case of chronic gout, the symptoms may become severe such as joint damage, loss of joint motion, and the formation of tophi.
Treatment Of Gout
The aim of treatment in gout is to provide rapid relief from pain and prevent acute attacks of gout. The effective treatment plan for acute gout incorporates NSAIDs, colchicine, and corticosteroids.
If the gout is caused by other clinical issues such as overweight, hypertension, increased liquor consumption, metabolic disorder of insulin obstruction, hyperinsulinemia, impeded glucose tolerance, and hypertriglyceridemia, then the aim of treatment is to treat the underlying cause.
Pharmacological measures ought to be consolidated with non-pharmacological measures like weight reduction, changes in diet, expanded exercise and diminished liquor utilization.
Treatment Of Acute Gout
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Commonly prescribed NSAIDs are indomethacin, diclofenac, ketorolac, naproxen, and piroxicam.
NSAIDs should be avoided in patients with heart failure, renal insufficiency, and a history of gastric ulceration. Care should also be exercised in elderly patients with multiple pathologies. When prescribing an NSAID, the need for gastric protection should be considered in patients at increased risk of a peptic ulcer, bleed, or perforation.
Colchicine
Colchicine is an alkaloid derived from the autumn crocus (colchicum autumnale) and has been reported to have been used in the treatment of gout since the 6th century AD.
Colchicine has a slower onset of action than NSAIDs but is recommended in patients where NSAIDs are contraindicated. It should be started as soon as possible after the onset of an attack.
Although the mode of action of colchicine in gout is not fully understood, it is thought to arrest microtubule assembly in neutrophils and inhibit many cellular functions. It suppresses monosodium urate crystal-induced NALP3 inflammasome-driven caspase-1 activation, IL-1β processing and release, and L-selectin expression on neutrophils.
Colchicine also blocks the release of a crystal-derived chemotactic factor from neutrophil lysosomes, blocks neutrophil adhesion to endothelium by modulating the distribution of adhesion molecules on the endothelial cells, and inhibits monosodium urate crystal-induced production of superoxide anions from neutrophils.
Corticosteroids
Corticosteroids are usually considered where the use of an NSAID or colchicine is contraindicated or in refractory cases. They may be given intravenously, intramuscularly, or directly into a joint (intra-articular) when only one or two joints are affected.
Interleukin-1 inhibitors
IL-1β is critically associated with the inflammatory response induced by monosodium urate crystals Anakinra, an IL-1 receptor antagonist, has been shown to reduce the pain of gout and bring about complete resolution. Other IL-1 inhibitors, such as rilonacept, are under development.
Treatment Of Chronic Gout
The standard treatment plan for chronic gout includes uric acid synthesis inhibitors (urostatic) and uricosuric drugs.
Uricostatic Agents
Uricostatic agents act on the enzyme xanthine oxidase. Xanthine oxidase catalyzes the oxidation of hypoxanthine to xanthine and subsequently xanthine to uric acid. Hypoxanthine comes from the catabolism of cellular nucleoproteins and purine nucleotides. Blocking the action of this enzyme reduces the production of uric acid.
Agents in this group include allopurinol and febuxostat.
Allopurinol
Allopurinol is the prophylactic agent of choice in the management of recurrent gout. To become pharmacologically active, allopurinol must be metabolized by the liver to oxypurinol. Oxypurinol has a much longer half-life than allopurinol, 14–16 h compared to 2 h. Both allopurinol and oxypurinol are renally excreted, with oxypurinol undergoing re-absorption from the renal tubule.
Febuxostat
Febuxostat is a more selective and potent inhibitor of xanthine oxidase than allopurinol and has no effect on other enzymes involved in purine or pyrimidine metabolism. It is licensed for the treatment of chronic hyperuricemia in conditions where urate deposition has already occurred including a history, or presence of, tophus and/or gouty arthritis.
Uricosuric Agents
Uricosuric agents increase uric acid excretion primarily by inhibiting post-secretory tubular absorption of uric acid from filtered urate in the kidney. They are indicated as second-line agents in those who are urate under-excretors and are dependent on the patient having an adequate level of renal function.
Probenecid, sulfinpyrazone, and benzbromarone are uricosuric drugs that increase the excretion of uric acid from the body.
Benzbromarone
Benzbromarone is effective in lowering serum urate levels and reducing the time to resolution of tophi. The risk of hepatotoxicity has been increased with this drug. For those who are prescribed benzbromarone, regular liver function tests must be performed during the first 6 months of therapy, and the hepatotoxic risk associated with the medicine should be clearly explained to the patient at the outset. The dose ranges from 50 to 200 mg daily.
Sulfinpyrazone
Sulfinpyrazone is effective in reducing the frequency of gout attacks, tophi, and plasma urate levels at doses of 200–800 mg/day. It has the same mode of action on the kidney as benzbromarone and probenecid all of which inhibit URAT-1 transporter resulting in reduced urate reabsorption. However,
Probenecid
Probenecid monotherapy is less effective than the other agents in this group and is generally not recommended. It may have a role as an add-on agent when allopurinol alone is insufficient. Doses of 0.5–2.0 g/day have been used.
Uricolytics
Uricolytic drugs convert uric acid to allantoin through the actions of the enzyme urate oxidase (uricase). Allantoin is more soluble than uric acid and readily excreted by the kidney.
Uricolytics are indicated for hyperuricemia associated with tumor lysis syndrome and are not indicated for other forms of hyperuricemia.
Rasburicase
Rasburicase, a recombinant form of the enzyme urate oxidase (uricase), is derived from a cDNA code from a modified Aspergillus flavus strain expressed in a modified strain of Saccharomyces cerevisiae. It is licensed to treat tumor lysis syndrome and is given intravenously at a dose of 0.2 mg/kg in short courses for 5–7 days.
Polyethylene Glycol-Uricase (PEG-Uricase)
PEG-uricase is a pegylated, recombinant form of uricase. Pegylation of the molecule reduces the risk of patients developing auto-antibodies and lengthens the half-life of the drug. It is effective in reducing tophi.
Prevention Of Gouty Flare
At the point when prophylactic treatment is started, there is a risk of precipitating an acute gout attack, or ‘mobilization flare’, for approximately 12 months. Mobilization flares are thought to be brought about by the quick fall in serum urate following the inception of urate bringing down. The danger of accelerating an acute gouty attack can be diminished by delaying the initiation of long-term urate-lowering therapy and endorsing colchicine or an NSAID during the treatment commencement period.
Colchicine is the agent of the first choice to prevent the precipitation of a flare when commencing chronic gout treatment. Low doses of colchicine (500 μcg orally twice a day) should be prescribed and continued for at least 6 months.
If there are no contraindications to the use of NSAIDs, they may be considered a second line to colchicine in patients' intolerant to colchicine. NSAIDs should be continued for a maximum of 6 weeks.