Gout

Gout is called an inflammatory disease in which monosodium urate crystals are deposited into a joint which makes it red, hot, tender, and swollen within a short period of time. When this happens it is called the Gouty Attack. The underlying cause is hyperuricemia, which is too much uric acid in the blood which results in the formation of sharp needle-like crystals in the areas with slow blood flow like the joints and the kidney tubules. If we observe repeated Gout Attacks over time it can cause destruction of the joint tissue which results in arthritis. If we need to understand where the uric acid comes from, first let us start with pyrimidines which together with purines are said to be nature’s most common nitrogen-containing heterocycles. A heterocycle is a molecular ring with different types of atoms. Purines, as well as pyrimidines, are key components of nucleic acid-like DNA and RNA. When cells along with the nucleic acid in those cells are broken down throughout the body, those purines are converted into uric acid. 

A molecule that can then be filtered out of the blood and excreted into the urine. Uric acid has limited solubility in body fluids, hyperuricemia occurs when the level of uric acid exceeds the rate of its solubility which is about 6.8 mg/dL. At a physiologic pH of about 7.4, uric acid loses a proton and becomes a urate ion, which then binds with sodium to form monosodium urate crystals. These crystals can form as a result of an increase in the consumption of purines, like from consuming purine-rich foods like shellfish, anchovies, red meat, or organ meat. They can be a result caused by the increase in the production of purines, for example, in the case of high-fructose corn syrup which contains beverages that could lead to forming uric acid which leads to the increasing purine synthesis. 

The other way in which the crystals could form is by the decreased clearance of uric acid, which is a cause of dehydration, due to not drinking enough quantity of water which is required or from consumption of alcoholic beverages, both allowing uric acid to precipitate out. Regularly eating these kinds of food can also lead to obesity and diabetes, both of which are risk factors for gout. 

Hyperuricemia can also develop as a result of chemotherapy or radiation treatment since cells die at a faster than the normal rate. Also, the case wherein some of these individuals have a genetic predisposition to the overproduction of uric acid, it is reversed with others with chronic kidney disease may be unable to excrete uric acid. There are some medications like thiazide diuretics and aspirin which can also increase the levels of uric acid and therefore the risk of gout. Now gout most often affects the first metatarsal joint of the foot or the base of the big toe and when it does the condition is called Podagra. Classically if we see in Podagra, here the person will wake up from sleep having a feeling like their big toe is on fire, for him/her even the weight of the sheets can be painful. 

The pain is most severe in the hours immediately following the attack and then generally lessens with time. But that discomfort and swelling can last for days or even for weeks. Gout can also affect other joints as well like those in the ankles, knees, wrists, and elbows. This type of inflammation and local pains which is caused by white blood cells or leukocytes also might migrate to the site to help eliminate uric acid and thereby release pro-inflammatory chemicals, including cytokines. If we see the treatment of gouty attack it is typically focused on decreasing the pain and swelling, this is most often with Nonsteroidal anti-inflammatory medications or NSAIDs, like naproxen sodium, or ibuprofen, but occasionally with corticosteroids as well. 

Colchicine which has anti-inflammatory effects by inhibiting white blood cell migration has also been used for a long time to treat gout attacks. To treat the underlying causes of increased uric acid though it is important to modify the diest, doing things like staying well hydrated using water, reducing and eliminating soda, alcohol, red meat, and seafood thereby staying active to ward off obesity. There are also medications that help to decrease the uric acid levels which include xanthine oxidase inhibitors like allopurinol. Xanthine oxidase is an enzyme that is involved in the breakdown of purines to uric acid, so inhibiting this enzyme results in less uric acid production. 

Uricosuric medication like probenecid increases the secretion of uric acid by the kidneys. Over a period of time, repeated gouty attacks can lead to a development of chronic gout which is a type of arthritis with the destruction of the joint tissue and permanent joint deformity. Chronic gout can eventually lead to permanent deposits of urate crystals called Tophi, which form along with the bones just beneath the skin. Individuals with chronic gout are also at an increased risk of developing kidney stones made of uric acid as well as urate nephropathy, which is when the urate crystals deposit in the interstitium of the kidney.   

Gout is an arthritic disease of your joints caused by too much uric acid in your body. In a normal condition your liver processes various substances in your body which includes purines, which are components of genetic material that are found both inside your cells and in some of the food that we eat. At the time when your liver breaks down purines, there is a waste product that will be produced which is called uric acid. Your body disposes of this waste through your kidneys, which will later remove it from your blood. At the time when the liver produces too much uric acid or the kidneys do not remove the required quantity of the uric acid from your body, which results in the excess amount of uric acid getting accumulated in the blood thereby leading to a condition called hyperuricemia. Having a lot of caffeinated beverages will affect the waste removal function of your kidneys causing an increase in the urine output which tends to eliminate too much water from our body which is a medical condition called dehydration. 

This intern will result in a much higher concentration of uric acid, which will be seen in the fluids of our body. Consider a case where the concentration of the uric acid is too high considering any of these sources, it will not be able to be in a dissolved state, during which this excess amount of the uric acid begins forming needle-like crystals inside of your joints, which is most commonly seen in the big toe. This formation of the uric acid crystals thereby leads to an inflammatory response. To counter this the white blood cells from your immune system will attack this uric acid crystal, which leads to pain in the joint and inflammation. This is what is called an acute gout attack if this condition is left untreated the uric acid levels will result in the lumpy deposits of the uric acid around your joint which is called Tophus. Which later leads to additional joint pain and also might lead to disfigurement.                               

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Hyperuricemia Causes and Risk Factors of Gout

The conditions that lead to hyperuricemia or gout are as follows

1. Enzyme defects which result in overproduction of uric acid.

2. Diet, this is a cause due to the overconsumption of purines.

3. Renal failure, this cases a lack of uric acid secretion.

4. Cancer treatment, due to chemo or radiation which causes the death of the cell.

5.  Diabetes and obesity, which bring about more of an acidic environment that favors uric acid deposition. 

Treatment

The anti-gout medication typically fall into 2 category

1. Those used to treat the pain and inflammation associated with an acute gout attack. The immediate swelling and pain caused by the excess food and drinks, which raises the uric acid levels. 

2. Those used to lower uric acid concentration in the blood to help prevent a gout attack, the lowering of the levels is carried out through medications.

Acute Gout Treatment

Rich food and alcohol are often a part of celebrations. Unfortunately after all the enjoyment, an unfortunate thing can occur for people at risk, a bad gout attack. Certain foods and alcohol drinks contain high levels of purines, which then produce high levels of uric acid when broken down in the body. The uric acid crystallizes and forms around the joint causing severe pain. So in order to treat this problem to ensure that it does not keep occurring again, we require the above 2 treatment methods mentioned. Pharmacological treatment is critical for gout attack and anti-inflammatory should be given within 24 hours of the onset to be most effective. 

The goal of these medications is to decrease pain and swelling of the joints affected. The choice of which agent you will be prescribed depends on the severity of the symptoms, the number of joints involved, and any other medical issues that the patient has. Your physician will be able to talk to you about your treatment options. Let's get to know about the medications you may be prescribed for treating acute gout attacks. Nonsteroidal anti-inflammatory drugs or NSAIDs are frequently used to quickly relieve the pain and swelling of an acute gout episode. Especially if taken at a full dose in the first 24 hours. Commonly used NSAIDs are ibuprofen, indomethacin, naproxen, COX-2 inhibitors such as celecoxib, which can be used in patients with gastrointestinal contraindications or intolerance to NSAIDs. 

Side effects can include stomach pain and heartburn, stomach ulcers, high blood pressure, liver and kidney problem, and a tendency to bleed. Treatment should be continued until the acute gouty attack completely resolves. Colchicine is another prescription and anti-inflammatory medication, which can be given as several doses in succession initially, followed by a daily dose until the attack is resolved. 

Colchicine’s most common side effects are diarrhea, nausea, and abdominal cramps. But most severe side effects can occur at high doses. To avoid side effects, lower doses are much better received and may be used in combination with NSAIDs. In patients with contraindications to these other agents, corticosteroids or steroids are the next choices. It can be administered as an injection into the infected joint called intra-articular are given systemically such as orally, with things such as prednisone or Medrol. Intra-articular steroids are useful if only one or two joints are affected. This modality could be used in combination with oral steroids, NSAIDs, or colchicine. 

Some side effects of systemic steroids include difficulty sleeping, elevated blood sugar, high blood pressure, and weight gain. These types of agents are used not only to resolve an attack of acute inflammation but also to prevent it from ever occurring, called prophylaxis. Although these are teg types of agents people often consider as a gout treatment. One must remember that they only work to resolve the effects of inflammation from gout and not treat the actual reason for gout which is the high levels of uric acid.

Chronic Gout Treatment

A gout attack that comes on suddenly and abruptly needs to be seen by a physician in the first 24 hours of its onset. Your doctor will immediately prescribe you medications that elevate your acute gout attack or the immediate swelling and pain caused by a sharp increase in your uric acid levels. But that is not where the treatment phase ends, we also need to treat the actual cause of the gout attack, the high levels of uric acid in the blood, to prevent the chronic effects of gout. 

It is important to remember that uric acid is the compound in the body responsible for the development of gout and is a natural product of the breakdown of many foods and even the cells in our body. In someone that has large deposits of gout in the body called Tophi has at least 2 attacks of gout per year and has chronic kidney disease or a history of kidney stones composed of uric acid. We just start them on the uric acid lowering therapy, the goal is to lower down the uric acid level to less than 6 and maintain it there. This is what decreases the existing burden of uric acid and prevents more uric acid from building up in the joints and damaging them. 

The methods used for urate-lowering therapy are as follows. It is important to know that all of these agents can put you at risk for a gout flare, particularly when they are first started due to shifts in the uric acid level. Allopurinol is a well established and commonly used drug and is one of the first lines of treatment for gout. It is under the class of xanthine oxidase inhibitors. These work by decreasing uric acid production and are widely available, efficacious, and affordable. The side effects include gastrointestinal distress, rashes in a rare but severe type of allergic reaction called Stevens-Johnson Syndrome, and Allopurinol Hypersensitivity Syndrome. 

The latter has been implicated in patients with renal impairment and concurrent use of diuretics such as thiazide and is more common in people with a certain ethnic background. Febuxostat is from the same class of drugs as allopurinol and is a xanthine oxidase inhibitor as well. It is well tolerated and comparable with efficacy to allopurinol and is safe with patients with renal impairment. Side effects include diarrhea, nausea, and elevation of liver enzymes. Increased gout flare has been reported with high doses and is usually expected in the first month of treatment. Probenecid is a uricosuric agent. 

Uricosuric is the second class of uric acid lowering treatment. They lower uric acid levels through increased secretion in the kidney. These agents increase the risk of uric acid stones and are contraindicated in those with a history of kidney stones. It can be used alone or as an adjunct to xanthine oxidase inhibitors. The allergic reaction can occur with probenecid and should be used in caution with patients with G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency and peptic ulcer disease. Several drug interactions also exist, whereby concurrent use of probenecid may increase blood levels of drugs or diminish their efficacy. 

Lesinurad is a recently approved uricosuric which increases the uric acid excretion by working on the uric acid transporter in the kidneys. It is approved for use in combination with xanthine oxidase inhibitors such as allopurinol for hyperuricemia. It is shown to decrease tophus formation and a lower likelihood of gout flares associated with a sustained decrease in serum is acid. The most common adverse effects include headache, influenza, and reflux disease. It can also increase creatinine levels, renal stones, and other renal related adverse events that have occurred. Duzallo, this is the newest gout treatment that has become available in the market and it combines both allopurinol and lesinurad in one pill. This is indicated in patients who have not achieved the goal level of uric acid from allopurinol alone. 

The most common adverse effects were headache, influenza, increased creatinine levels, as well as reflux, similar to side effects from the individual component of allopurinol and lesinurad. Pegloticase is a recombinant enzyme that breaks down uric acid in the body into a form that is easily excretable in the urine. This medication is given as an IV infusion every 2 weeks and is been approved by the FDA (Food and Drug Administration) for gout that is refractory to conventional treatment including deforming tophaceous gout. This medication can lead to a rapid reduction in uric acid burden in the body and a faster dissolution of tophi and can be used with patients with renal and liver impairment. However, infusion reaction and development of antibodies against the medication leading to the loss of efficacy can occur. The patient should not be on any other urate-lowering agent at the time of infusions and close monitoring of the serum uric acid levels should be done prior to each infusion. If a uric acid greater than 6 is seen twice before subsequent infusions, it is recommended that the infusion be stopped so as to prevent side effects.