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Gout

Disease Details

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Description: Gout is a type of arthritis characterized by sudden, severe attacks of pain, swelling, redness, and tenderness in the joints, often at the base of the big toe.
Type: Gout is a form of inflammatory arthritis. It does not follow a specific Mendelian pattern of genetic transmission but has a complex genetic component influenced by multiple genes and environmental factors. It is often associated with variations in genes such as SLC2A9 and ABCG2 that affect uric acid metabolism.
Signs And Symptoms: Gout can present in several ways, although the most common is a recurrent attack of acute inflammatory arthritis (a red, tender, hot, swollen joint). The metatarsophalangeal joint at the base of the big toe is affected most often, accounting for half of cases. Other joints, such as the heels, knees, wrists, and fingers, may also be affected. Joint pain usually begins during the night and peaks within 24 hours of onset. This is mainly due to lower body temperature. Other symptoms may rarely occur along with the joint pain, including fatigue and high fever.Long-standing elevated uric acid levels (hyperuricemia) may result in other symptoms, including hard, painless deposits of uric acid crystals called tophi. Extensive tophi may lead to chronic arthritis due to bone erosion. Elevated levels of uric acid may also lead to crystals precipitating in the kidneys, resulting in kidney stone formation and subsequent acute uric acid nephropathy.
Prognosis: Without treatment, an acute attack of gout usually resolves in five to seven days; however, 60% of people have a second attack within one year. Those with gout are at increased risk of hypertension, diabetes mellitus, metabolic syndrome, and kidney and cardiovascular disease and thus are at increased risk of death. It is unclear whether medications that lower urate affect cardiovascular disease risks. This may be partly due to its association with insulin resistance and obesity, but some of the increased risk appears to be independent.Without treatment, episodes of acute gout may develop into chronic gout with destruction of joint surfaces, joint deformity, and painless tophi. These tophi occur in 30% of those who are untreated for five years, often in the helix of the ear, over the olecranon processes, or on the Achilles tendons. With aggressive treatment, they may dissolve. Kidney stones also frequently complicate gout, affecting between 10 and 40% of people, and occur due to low urine pH promoting the precipitation of uric acid. Other forms of chronic kidney dysfunction may occur.
Onset: Gout typically has a sudden onset, often at night, with severe pain, swelling, redness, and warmth in the affected joint, commonly the big toe.
Prevalence: Gout is a common form of inflammatory arthritis. The prevalence of gout varies by population but is generally increasing worldwide. In the United States, the prevalence is approximately 3.9%, affecting around 9.2 million adults. It tends to be more common in men than in women, particularly affecting those over the age of 40. Factors such as diet, genetic predisposition, and comorbid conditions like hypertension and obesity contribute to its prevalence.
Epidemiology: Gout affects around 1–2% of people in the Western world at some point in their lifetimes and is becoming more common. Some 5.8 million people were affected in 2013. Rates of gout approximately doubled between 1990 and 2010. This rise is believed to be due to increasing life expectancy, changes in diet and an increase in diseases associated with gout, such as metabolic syndrome and high blood pressure. Factors that influence rates of gout include age, race, and the season of the year. In men over 30 and women over 50, rates are 2%.In the United States, gout is twice as likely in males of African descent than those of European descent. Rates are high among Polynesians, but the disease is rare in aboriginal Australians, despite a higher mean uric acid serum concentration in the latter group. It has become common in China, Polynesia, and urban Sub-Saharan Africa. Some studies found that attacks of gout occur more frequently in the spring. This has been attributed to seasonal changes in diet, alcohol consumption, physical activity, and temperature.
Intractability: Gout is not generally considered intractable. It can often be managed effectively with a combination of medication, lifestyle changes, and dietary modifications. Treatments aim to control pain during flare-ups and reduce uric acid levels to prevent future attacks. However, if left untreated, it can lead to more severe and chronic problems.
Disease Severity: Disease severity for gout can vary widely among individuals. Gout often presents as acute, sudden, and severe attacks of pain, swelling, redness, and tenderness in the joints, particularly the big toe. Without proper treatment, gout can lead to chronic arthritis and tissue damage. The severity may also be influenced by factors such as the duration of untreated hyperuricemia (high uric acid levels), frequency of gout attacks, and individual response to treatment.
Healthcare Professionals: Disease Ontology ID - DOID:13189
Pathophysiology: Gout is a disorder of purine metabolism, and occurs when its final metabolite, uric acid, crystallizes in the form of monosodium urate, precipitating and forming deposits (tophi) in joints, on tendons, and in the surrounding tissues. Microscopic tophi may be walled off by a ring of proteins, which blocks interaction of the crystals with cells and therefore avoids inflammation. Naked crystals may break out of walled-off tophi due to minor physical damage to the joint, medical or surgical stress, or rapid changes in uric acid levels. When they break through the tophi, they trigger a local immune-mediated inflammatory reaction in macrophages, which is initiated by the NLRP3 inflammasome protein complex. Activation of the NLRP3 inflammasome recruits the enzyme caspase 1, which converts pro-interleukin 1β into active interleukin 1β, one of the key proteins in the inflammatory cascade. An evolutionary loss of urate oxidase (uricase), which breaks down uric acid, in humans and higher primates has made this condition common.The triggers for precipitation of uric acid are not well understood. While it may crystallize at normal levels, it is more likely to do so as levels increase. Other triggers believed to be important in acute episodes of arthritis include cool temperatures, rapid changes in uric acid levels, acidosis, articular hydration and extracellular matrix proteins. The increased precipitation at low temperatures partly explains why the joints in the feet are most commonly affected. Rapid changes in uric acid may occur due to factors including trauma, surgery, chemotherapy and diuretics. The starting or increasing of urate-lowering medications can lead to an acute attack of gout with febuxostat of a particularly high risk. Calcium channel blockers and losartan are associated with a lower risk of gout compared to other medications for hypertension.
Carrier Status: Gout is not associated with a carrier status. It is a type of arthritis caused by elevated levels of uric acid in the blood, leading to the formation of urate crystals in the joints. It can be influenced by genetic factors, lifestyle, and other health conditions, but it is not a condition where you have a carrier status similar to some genetic disorders.
Mechanism: Gout is a form of inflammatory arthritis characterized by sudden, severe attacks of pain, redness, and tenderness in joints. It is primarily caused by elevated levels of uric acid in the blood, a condition known as hyperuricemia.

**Mechanism:**
1. **Hyperuricemia:** Excessive production or insufficient excretion of uric acid leads to its accumulation in the bloodstream.
2. **Crystal Formation:** When blood levels of uric acid are overstaturated, urate crystals (monosodium urate) form and deposit in joints, tendons, and surrounding tissues.
3. **Inflammatory Response:** The immune system recognizes these crystals as foreign, triggering an inflammatory response. Neutrophils, a type of white blood cell, are particularly active in this response.
4. **Symptom Manifestation:** The inflammatory response causes swelling, redness, and intense pain in the affected joint, commonly the big toe, but it can occur in other joints as well.

**Molecular Mechanisms:**
1. **NLRP3 Inflammasome Activation:** The deposited urate crystals activate the NLRP3 inflammasome, a multi-protein complex within innate immune cells like macrophages.
2. **Caspase-1 Activation:** This activation leads to the conversion of procaspase-1 into active caspase-1.
3. **IL-1β Processing and Release:** Active caspase-1 processes pro-inflammatory cytokines such as pro-IL-1β into their active form, IL-1β, which is then released into the extracellular environment.
4. **Recruitment of Immune Cells:** IL-1β plays a critical role in recruiting additional immune cells, particularly neutrophils, to the site of crystal deposition.
5. **Inflammation Amplification:** The recruited cells release more pro-inflammatory mediators, perpetuating the cycle of inflammation and leading to the clinical symptoms of gout.

These processes highlight the intricate balance between metabolic function and immune response that, when disrupted, results in the painful and debilitating manifestations of gout.
Treatment: The initial aim of treatment is to settle the symptoms of an acute attack. Repeated attacks can be prevented by medications that reduce serum uric acid levels. Tentative evidence supports the application of ice for 20 to 30 minutes several times a day to decrease pain. Options for acute treatment include nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and glucocorticoids. While glucocorticoids and NSAIDs work equally well, glucocorticoids may be safer. Options for prevention include allopurinol, febuxostat, and probenecid. Lowering uric acid levels can cure the disease. Treatment of associated health problems is also important. Lifestyle interventions have been poorly studied. It is unclear whether dietary supplements have an effect in people with gout.
Compassionate Use Treatment: For gout, physicians sometimes consider compassionate use treatments as well as off-label or experimental treatments when conventional therapies are ineffective or unsuitable for a patient.

### Compassionate Use Treatment:
Compassionate use allows patients access to investigational drugs that are not yet approved by regulatory bodies but show promise in treating certain conditions. For gout, this might include:

1. **Biologic agents**: Anakinra (an interleukin-1 inhibitor) has shown potential in some gout cases but is generally used under compassionate use protocols.

### Off-Label Treatments:
Off-label use involves prescribing drugs approved for other conditions but found to be effective for gout in some cases.

1. **Losartan**: Primarily used for hypertension, losartan can help lower uric acid levels.
2. **Fenofibrate**: A lipid-lowering agent that can also reduce uric acid levels.
3. **Probenecid**: While approved for gout, it’s not commonly the first line of treatment but can be effective off-label when other treatments fail.

### Experimental Treatments:
These are generally part of clinical trials and are being studied for their efficacy and safety in treating gout.

1. **Arhalofenate**: A dual-acting anti-inflammatory and uricosuric agent is currently being investigated.
2. **SEL-212**: A combination of an enzyme that breaks down uric acid and a protein designed to reduce immune responses against the enzyme.

Patients considering these options should do so under the guidance of their healthcare provider.
Lifestyle Recommendations: ### Lifestyle Recommendations for Gout:

1. **Dietary Changes**:
- **Avoid Purine-Rich Foods**: Limit intake of red meat, organ meats, and certain seafood (like sardines and mackerel) which are high in purines.
- **Limit Alcohol**: Reduce or eliminate alcohol consumption, especially beer and spirits.
- **Stay Hydrated**: Drink plenty of water to help flush uric acid from the body.
- **Limit Sugary Foods and Drinks**: Avoid high-fructose corn syrup and sugary beverages.
- **Increase Low-Fat Dairy Intake**: Some studies suggest that low-fat dairy products can help lower uric acid levels.

2. **Weight Management**:
- **Achieve and Maintain a Healthy Weight**: Obesity increases the risk of gout; losing weight can help lower uric acid levels.
- **Avoid Crash Diets and Rapid Weight Loss**: These can increase uric acid levels and trigger gout attacks.

3. **Physical Activity**:
- **Regular Exercise**: Engage in moderate physical activity to maintain a healthy weight and improve overall health.

4. **Medication and Monitoring**:
- **Take Medications as Prescribed**: If you're on medication for gout, adhere strictly to your doctor's prescription.
- **Regular Check-Ups**: Keep regular appointments with your healthcare provider to monitor uric acid levels and adjust treatment as needed.

5. **Avoid Certain Medications**:
- **Be Wary of Diuretics and Aspirin**: Some medications can increase uric acid levels; consult with your doctor for alternatives if needed.

6. **Stress Management**:
- **Reduce Stress**: High stress levels can exacerbate gout symptoms, so practice stress-reducing techniques like yoga, meditation, and deep breathing exercises.
Medication: As of 2020, allopurinol is generally the recommended preventative treatment if medications are used. A number of other medications may occasionally be considered to prevent further episodes of gout, including probenecid, febuxostat, benzbromarone, and colchicine. Long term medications are not recommended until a person has had two attacks of gout, unless destructive joint changes, tophi, or urate nephropathy exist. It is not until this point that medications are cost-effective. They are not usually started until one to two weeks after an acute flare has resolved, due to theoretical concerns of worsening the attack. They are often used in combination with either an NSAID or colchicine for the first three to six months.While it has been recommended that urate-lowering measures should be increased until serum uric acid levels are below 300–360 µmol/L (5.0–6.0 mg/dl), there is little evidence to support this practice over simply putting people on a standard dose of allopurinol. If these medications are in chronic use at the time of an attack, it is recommended that they be continued. Levels that cannot be brought below 6.0 mg/dl while attacks continue indicates refractory gout.While historically it is not recommended to start allopurinol during an acute attack of gout, this practice appears acceptable. Allopurinol blocks uric acid production, and is the most commonly used agent. Long term therapy is safe and well-tolerated and can be used in people with renal impairment or urate stones, although hypersensitivity occurs in a small number of individuals. The HLA-B*58:01 allele of the human leukocyte antigen B (HLA-B) is strongly associated with severe cutaneous adverse reactions during treatment with allopurinol and is most common among Asian subpopulations, notably those of Korean, Han-Chinese, or Thai descent.Febuxostat is only recommended in those who cannot tolerate allopurinol. There are concerns about more deaths with febuxostat compared to allopurinol. Febuxostat may also increase the rate of gout flares during early treatment. However, there is tentative evidence that febuxostat may bring down urate levels more than allopurinol.Probenecid appears to be less effective than allopurinol and is a second line agent. Probenecid may be used if undersecretion of uric acid is present (24-hour urine uric acid less than 800 mg). It is, however, not recommended if a person has a history of kidney stones. Pegloticase is an option for the 3% of people who are intolerant to other medications. It is a third line agent. Pegloticase is given as an intravenous infusion every two weeks, and reduces uric acid levels. Pegloticase is useful decreasing tophi but has a high rate of side effects and many people develop resistance to it. Using lesinurad 400 mg plus febuxostat is more beneficial for tophi resolution than lesinural 200 mL with febuxostat, with similar side effects. Lesinural plus allopurinol is not effective for tophi resolution. Potential side effects include kidney stones, anemia and joint pain. In 2016, it was withdrawn from the European market.Lesinurad reduces blood uric acid levels by preventing uric acid absorption in the kidneys. It was approved in the United States for use together with allopurinol, among those who were unable to reach their uric acid level targets. Side effects include kidney problems and kidney stones.Diuretics have been associated with attacks of gout, but a low dose of hydrochlorothiazide does not seem to increase risk. Other medications that increase the risk include niacin, aspirin (acetylsalicylic acid), ACE inhibitors, angiotensin receptor blockers, beta blockers, ritonavir, and pyrazinamide. The immunosuppressive drugs ciclosporin and tacrolimus are also associated with gout, the former more so when used in combination with hydrochlorothiazide. Hyperuricemia may be induced by excessive use of Vitamin D supplements. Levels of serum uric acid have been positively associated with 25(OH) D. The incidence of hyperuricemia increased 9.4% for every 10 nmol/L increase in 25(OH) D (P < 0.001).
Repurposable Drugs: For gout, a disease characterized by the deposition of urate crystals in joints leading to inflammation and pain, several drugs originally developed for other conditions can be repurposed:

1. **Colchicine**: Initially used for familial Mediterranean fever, it is also effective in reducing inflammation in gout.
2. **Losartan**: An antihypertensive medication that has a mild uricosuric effect, helping to lower uric acid levels.
3. **Fenofibrate**: Typically prescribed for hyperlipidemia, it can reduce serum urate levels and may be beneficial for gout management.

These repurposable drugs can be considered for managing gout, especially in patients with comorbid conditions that these drugs might also help treat. Always consult a healthcare professional before starting any new treatment.
Metabolites: Gout is primarily associated with hyperuricemia, which involves elevated levels of uric acid (a metabolite) in the blood. The excessive uric acid can crystallize and deposit in joints, causing inflammation and intense pain.
Nutraceuticals: For gout, certain nutraceuticals may help manage the condition. These include:

1. **Cherry Extract**: Known to reduce uric acid levels and inflammation.
2. **Omega-3 Fatty Acids**: Found in fish oil, these may help reduce joint inflammation.
3. **Vitamin C**: May help lower uric acid levels in the blood.
4. **Turmeric**: Contains curcumin, which has anti-inflammatory properties.
5. **Ginger**: Known for its anti-inflammatory effects which may benefit gout sufferers.
6. **Devil's Claw**: Often used for its anti-inflammatory and pain-relieving properties.

It is important to consult with a healthcare provider before starting any new supplement regimen.
Peptides: Gout is an inflammatory arthritis caused by the deposition of monosodium urate crystals in joints due to elevated levels of uric acid in the blood. Peptides in the context of gout treatment or research often refer to bioactive molecules that can modulate inflammation or uric acid levels. Nanotechnology (nan.) in gout may involve creating nanoparticles for targeted drug delivery or imaging, enhancing therapeutic efficacy and reducing side effects.