[Overview]
Gout (gout) is a crystalline arthritis caused by disorders of purine metabolism and/or reduced uric acid excretion, and is characterized clinically by acute and chronic arthritis due to hyperuricemia and urate crystals deposition (gout stones). In addition to deposits in and around joints, tendons, gout stones can also be deposited in the kidneys and can lead to uric acid nephropathy, uric acid urinary tract stones, etc. In severe cases, renal insufficiency can occur. Gout is often associated with obesity, hyperlipidemia, diabetes, hypertension, and cardiovascular disease.
Gout is divided into two categories: primary and secondary. Primary gout has some family heritability, with about 20% of patients having a positive family history. Except for about 1% of primary gout caused by congenital enzyme defects, the cause of the majority of cases is unknown. Secondary gout occurs in the course of other diseases, such as renal disease, hematological disease, or due to a variety of reasons such as taking certain drugs or radiotherapy for tumors. This section focuses on primary gout.
Gout is seen in all regions of the world and in all ethnic groups. In Europe and the United States, the prevalence of hyperuricemia is 2% to 18% and gout is 0.13% to 0.37%. Epidemiological surveys in some areas of China have shown that the prevalence of hyperuricemia and gout in China has increased steeply in recent years, which may be related to the economic development, lifestyle and dietary changes in China.
[Clinical manifestations]
Ninety-five percent of gout patients are male, and the age of first attack is usually after 40 years old, but there is a trend of younger patients in recent years; most female patients appear after menopause. According to the natural course of gout, it can be divided into acute, intermittent and chronic phases.
1. Acute gouty arthritis: There may be no aura before the onset of the disease. Triggering factors include full meals and alcohol consumption, excessive fatigue, stress, localized joint injury, surgery, and exposure to cold and moisture. Acute monoarthritis or polyarticular pain that often strikes at night is usually the first symptom. The joint pain wakes up in the early morning, worsens progressively, and is severe like a knife cut or bite, with the pain peaking at 24-48 hours. Signs resemble an acute infection, with localized fever, redness, swelling, and significant dull pain. The pain resolves spontaneously within a few days or weeks. The first attack is usually monoarthritic, with 60-70% of patients having the first episode in the first metatarsophalangeal joint, and 90% of patients having recurrent involvement of this part later in the course of the disease. The arch, ankle, knee, wrist, and elbow joints are also common sites of attack. The systemic manifestations are fever, headache, nausea, palpitations, chills, discomfort and elevated white blood cells, and increased blood sedimentation.
2. Gout interval: After the acute attack of gout is relieved, there are usually no obvious sequelae, sometimes there is only deepening of skin pigmentation at the attack site, dark red or purplish red, flaking and itching, which is called asymptomatic interval. Most patients have a long interval (usually 1-2 years) after the initial attack, but the length of the interval varies greatly, and as the disease progresses the interval gradually shortens. Even the bursa around the joint, tendons, tendon sheaths and other places urate deposits, symptoms gradually atypical.
3, chronic arthritis phase: repeated deposition of uric acid salt makes local tissues occur chronic foreign body-like reaction, the deposit is surrounded by monocytes, epithelial cells, macrophages, fibrous tissue proliferation formed nodules, called gout stone. Gout stones are usually found 10 years after the onset of the disease and are a sign that the disease has become chronic, and can be found in joints, peri-articular areas, subcutaneous tissue and internal organs. They are typically found in the auricle, but also around the joints of the toes, fingers, wrists, ankles, elbows, etc. They are elevated under the skin and appear as yellowish-white sesame- to egg-sized bulges with a thin surface, which break down and expel a white powder or paste that does not heal over time, but is rarely secondary to infection. When gouty stone occurs in the joint, it can cause joint cartilage and bone erosion and destruction, reactive hyperplasia, peri-articular tissue fibrosis, persistent joint pain, swelling, ankylosis, deformity, and even fracture, called gouty stone chronic arthritis.
4. Renal lesions.
Renal pathology is almost always damaged in patients with gout, and about 1/3 of patients clinically present with renal symptoms, which can be seen at any time during the course of gout.
(1) Uric acid nephropathy: Deposition of urate crystals in renal tissue, especially in the renal medulla and conus, can lead to chronic interstitial nephritis, causing tubular deformation, atrophy, fibrosis and sclerosis, which in turn involves the glomerular vascular bed. It manifests as decreased renal tubular concentration function, increased nocturia, low specific gravity urine, hematuria, proteinuria, lumbago, edema, hypertension, and advanced renal insufficiency.
(2) Uric acid urinary stones: Increased uric acid concentration in the urine and deposition to form urinary stones, with a total incidence of about 20% in patients with gout, and may appear before the onset of gouty arthritis. Smaller stones are excreted in the urine in the form of gravel and may not be felt. Larger ones obstruct the urinary tract and cause renal colic, hematuria, pyelonephritis, and hydronephrosis. Due to the low pH of urine in gout patients, uric acid is mostly converted into uric acid, which is less soluble than uric acid, so it is easy to form pure uric acid stones, which often do not show up on X-ray, and a few of them can show stone shadows when mixed with calcium oxalate and calcium phosphate.
(3) Acute uric acid nephropathy: Mostly seen in secondary hyperuricemia, mainly seen after tumor radiotherapy and chemotherapy, blood and uric acid suddenly rise significantly, and a large number of uric acid crystals are deposited in renal tubules, collecting ducts, renal pelvis and ureter, causing extensive and severe urinary tract obstruction, manifested as oliguria, anuria, acute renal failure, and a large number of uric acid crystals and red blood cells are seen in urine.
[Diagnostic points]
The diagnosis of gout mainly relies on clinical manifestations, blood uric acid level, finding urate crystals and imaging examinations.
1. Symptoms.
(1) Sudden onset of joint redness, swelling and severe pain, involving the distal single joint of the limb, especially the first metatarsophalangeal joint is common, often peaking in about 24 hours and resolving on its own within a few days to weeks.
(2) Early trial of colchicine may provide rapid relief of symptoms.
(3) Full meals, alcohol consumption, overexertion, and local trauma are common triggers.
(4) The above-mentioned symptoms may recur, with no obvious symptoms in the interval.
(5) Gout stone nodules may appear under the skin.
(6) With the prolonged course of the disease, the affected joints may continue to be swollen and painful, and the movement may be limited.
(7) There may be renal colic, hematuria, history of urinary discharge stones or back pain, increased nocturia and other symptoms.
2. Physical signs.
(1) Acute monoarthritis manifestations, local skin tension, redness, swelling, burning and tenderness of the involved joints are obvious.
(2) Elevated body temperature in some patients.
(3) Intermittent absence of signs or only local skin pigmentation, desquamation, etc.
(4) Eccentric nodules around the auricle and joints with white powder-like or paste-like overflow when they break down and do not heal over time.
(5) Persistent swelling, pressure pain, deformity or even fracture of the involved joints in the chronic phase.
(6) It may be accompanied by edema, hypertension, and painful percussion in the kidney area.
3.Auxiliary examination
(1) Measurement of blood uric acid: the most widely used method is the uric acid enzyme method. It is 210-416µmol/l (3.5-7.0mg/dl) for men; 150-357µmol/l (2.5-6.0mg/dl) for women, close to men after menopause . Under the physiological conditions of 37℃ and pH 7.4, the solubility of urate is about 6.4mg/dl, plus the binding of urate to plasma protein is about 0.4mg/dl, the saturation of urate in blood is about 7.0mg/dl, blood uric acid ≥416µmol/l (7.0mg/dl) is hyperuricemia. . Because blood uric acid is affected by many factors and there is volatility, it should be measured repeatedly.
When blood uric acid continues to be high or fluctuates sharply, blood uric acid in a supersaturated state will crystallize and deposit in the tissues, causing signs and symptoms of gout. In addition, factors affecting uric acid solubility, such as decreased estrogen levels, decreased binding of uric acid to plasma proteins, and decreased local temperature and pH, can also contribute to the precipitation of uric acid salts. Thus, hyperuricemia is the most important biochemical basis for the development of gout. However, only about 10% of those with persistently high blood uric acid levels develop gout, mostly asymptomatic hyperuricemia, while a small percentage of gout patients have normal blood uric acid during acute arthritic episodes, indicating both the complexity of the causes of gout and the fact that hyperuricemia and gout are two concepts that should be distinguished.
(2) Determination of uric acid: After 5 days of low purine diet, 24-hour urine was collected and tested by uric acid enzyme method. The normal level is 1.2-2.4mmol (200-400mg), more than 3.6mmol (600mg) is the type of excessive uric acid production, which only accounts for a minority; most of them are less than 3.6mmol (600mg) is the type of reduced uric acid excretion. In fact, many patients have both defects and one of them is predominant. Through uric acid measurement, the typing of hyperuricemia can be initially determined, which can help the selection of uric acid-lowering drugs and the identification of the nature of urinary stones.
(3) Synovial fluid and gout stone examination: During the acute arthritis period, joint puncture is performed to extract synovial fluid, and under the polarized light microscope, there are negative double refractive needle-like urate crystals in the synovial fluid or within the leukocytes, and the positive rate is about 90%. The same pattern of urate crystals can also be found in puncture or biopsy of gout stone contents. This test has a confirmatory significance and should be considered the “gold standard” for gout diagnosis.
(4) X-ray examination: soft tissue swelling can be seen in the acute arthritis stage; in the chronic arthritis stage, joint space narrowing, joint surface irregularity, gouty stone deposition, and typically round chisel-like or worm-eaten defects in the bone, sharp hyperplastic calcification at the edges, and dislocation and fracture in severe cases.
(5) Ultrasonography: Since most uric acid urinary tract stones do not show up on X-ray, renal ultrasonography is feasible. Renal ultrasonography can also understand the extent of kidney damage.
4.Diagnostic methods
(1) Acute gouty arthritis
Acute gouty arthritis is the main clinical manifestation of gout and is often the first symptom, therefore, the diagnosis of the acute phase of gout is very important. At present, the 1977 American College of Rheumatology (ACR) classification criteria (see Table 1) or the 1985 Holmes criteria (see Table 2) are mostly used for diagnosis. It should also be differentiated from rheumatic fever, dengue, cellulitis, septic arthritis, traumatic arthritis, and pseudogout.
Table 1, 1977 ACR classification criteria for acute gouty arthritis
1, specific urate crystals in the joint fluid, or
2.The presence of urate crystals in gout stones confirmed by chemical methods or polarized light microscopy, or
3.With 6 of the following 12 items (clinical, laboratory and X-ray manifestations)
(1) Acute arthritis attack > 1 time
(2) Inflammatory response peaks within 1 day
(3) Monoarthritis attack
(4) Redness of the joint is visible
(5) Pain or swelling of the first metatarsophalangeal joint
(6) Unilateral involvement of the first metatarsophalangeal joint
(7) Unilateral tarsal joint involvement
(8) Suspected gout stone
(9) Hyperuricemia
(10) Asymmetric intra-articular swelling (confirmed by X-ray)
(11) Subcortical cyst without bone erosion (confirmed by X-ray)
(12) Negative microbiological culture of joint fluid at the onset of arthritis
Table 2, 1985 Holmes criteria
Those with 1 of the following
1. Leukocytes in synovial fluid with phagocytosis of urate crystals
2. A large number of urate crystals on a puncture or nodal biopsy of the joint cavity fluid
3. Recurrent acute monoarthritis and asymptomatic interval, hyperuricemia, and colchicine
Those who are effective in colchicine treatment
(2) Intermittent gout
This period is the remission state between repeated acute attacks, usually without any discomfort or with only mild joint symptoms, therefore, the diagnosis of this period must rely on the past history of acute gouty arthritis attacks and hyperuricemia.
(3) Chronic gout
Chronic stage gout is a consequence of a disease that has been prolonged for many years with persistently high blood uric acid levels that have not been satisfactorily controlled, and the clinical features of this stage are gout stone formation or persistent failure to relieve joint symptoms. Combined with X-ray or nodal biopsy to find uric acid crystals, it is not difficult to diagnose. This stage should be differentiated from rheumatoid arthritis, psoriatic arthritis and bone tumors.
(4) Renal lesions
Patients with urate nephropathy initially show an increase in nocturia, followed by a decrease in urine specific gravity, hematuria, mild to moderate proteinuria, and even renal insufficiency. At this point, it should be distinguished from secondary gout caused by kidney disease. In the case of uric acid urinary tract stones, renal colic and hematuria are the main clinical manifestations, and most of them do not show up on X-ray plain film, while ultrasound examination may reveal them. Acute uric acid nephropathy should be considered in patients with widespread tumor dissemination or receiving radiotherapy for sudden onset of acute renal failure, which is characterized by an acute and marked increase in blood uric acid at an early stage.
[Treatment options and principles]
Primary gout lacks etiological treatment, so it cannot be cured. The objectives of treatment are: (1) to rapidly control the acute attack of gouty arthritis; (2) to prevent the recurrence of acute arthritis; (3) to correct hyperuricemia in order to prevent joint destruction and kidney damage caused by urate deposition; (4) to surgically remove gouty stones and perform orthopedic surgery on destroyed joints in order to improve the quality of life.
1.General treatment
(1) Diet control: Gout patients should adopt low-calorie diet and maintain ideal body weight, meanwhile, avoid high purine food. Foods containing more purines mainly include animal offal, sardines, clams, oysters and other seafood and thick meat soup, followed by fish and shrimp, meat, peas, etc., while various cereal products, fruits, vegetables, milk, dairy products, eggs, etc. contain the least purines. Strictly abstain from drinking various kinds of alcohol and drink more than 2000ml of water daily.
(2) Avoid causative factors: avoid overeating and alcoholism, cold and damp, excessive fatigue and mental tension, wear comfortable shoes, prevent joint injuries, and use drugs that affect uric acid excretion, such as certain diuretics and small doses of aspirin, etc. with caution.
(3) Prevention and control of concomitant diseases: treat concomitant hyperlipidemia, diabetes, hypertension, coronary heart disease, cerebrovascular disease, etc. at the same time.
2. Treatment of acute gouty arthritis: bed rest, elevation of the affected limbs, avoid weight bearing. Withhold the use of uric acid-lowering drugs to avoid causing fluctuations in blood uric acid, prolonging attacks or causing metastatic gout.
(1) Colchicine: It can inhibit inflammatory cell chemistry and is effective in stopping inflammation and relieving pain. If the digestive tract cannot tolerate colchicine, it can be given intravenously by diluting colchicine 1mg with 0.9% sodium chloride solution. It is worth noting that the therapeutic dose of colchicine is very close to the toxic dose, and in addition to gastrointestinal reactions, there may be leukopenia, aplastic anemia, hepatocyte damage, hair loss, etc. It should be used with caution in cases of renal insufficiency.
(2) Non-steroidal anti-inflammatory drugs (NSAIDs): Used more often than colchicine for acute attacks, usually starting with a full dose and reducing it after the symptoms are relieved. The most common side effects are gastrointestinal symptoms, which may also aggravate renal insufficiency and affect platelet function, etc. It is contraindicated in active peptic ulcers.
(3) Glucocorticoids: Usually used for those whose colchicine and NSAIDs are ineffective or cannot be tolerated. ACTH 25μ intravenous drip or 40~80μ intramuscular injection, repeat if necessary; or oral prednisone 20-30mg daily, gradually reduce the dose and stop after 3-4 days.
3. Treatment of intermittent and chronic phase: aimed at controlling blood uric acid at normal level. Uric acid-lowering drugs are divided into two categories, one is pro-uric acid excretory drugs and the other is inhibiting uric acid production drugs, both of which have positive efficacy. In order to prevent acute arthritis induced by rapid reduction of blood uric acid after medication, it should be started from a small dose, gradually increased to the therapeutic amount, and then changed to maintenance amount after taking effect, so that the blood uric acid is maintained below 327µmol/l (5.5mg/dl) for a long time. In addition to prevent acute attacks, colchicine 0.5mg can also be taken prophylactically once or twice daily while starting uric acid-lowering drugs, or non-steroidal anti-inflammatory drugs can be used. Two types of uric acid-lowering drugs can be combined in the following cases: poor effect of one type of drug alone, blood uric acid >535µmol/l (9.0mg/dl), massive formation of gout stones.
(1) Pro-uric acid excretory drugs: inhibit the reabsorption of uric acid in the proximal renal tubules to facilitate uric acid excretion. Since most gout patients belong to the type with reduced uric acid excretion, one of the following drugs can be preferred for patients with normal or mildly abnormal renal function (not effective when endogenous creatinine clearance <30ml/min), no urinary stones and uric acid nephropathy. Take alkaline medication such as sodium bicarbonate 1~2g 3 times a day or alkaline combination 10ml 3 times a day to keep urine pH around 6.5 (but not too alkaline to prevent calcium stone formation), and drink plenty of water to maintain urine output.
①Probenecid: 0.25g twice a day, gradually increase to 0.5g 3 times a day. Major side effects: gastrointestinal reactions, rash, allergic reactions, bone marrow suppression, etc. It is contraindicated for those who are allergic to sulfonamide.
Main side effects: gastrointestinal reactions, rash, bone marrow suppression, etc. Occasionally, nephrotoxic reactions may occur. This drug has a mild water retention effect and should be used with caution in patients with chronic cardiac insufficiency.
Benzbromarone: A new type of uric acid excretory drug. 50mg once a day, gradually increase to 100mg once a day. Main side effects: Gastrointestinal reactions such as diarrhea, rash, allergic conjunctivitis and granulocytopenia are occasionally seen.
(2) Inhibition of uric acid production: Inhibit xanthine oxidase, block the conversion of xanthine into uric acid and reduce uric acid production. It is used for hyperuricemia with excessive production of uric acid or for those who are not suitable for the use of uric acid excretory drugs, and also for secondary gout.
Allopurinol: 100mg once a day, gradually increase to 100mg~200mg 3 times a day. 300mg or less can be taken once a day, more than 300mg can be taken orally in divided doses. Main side effects: gastrointestinal reactions, rash, drug fever, bone marrow suppression, hepatic and renal impairment, etc. Occasionally, serious toxic reactions may occur. For those with renal insufficiency, the dosage should be reduced. Liver and kidney function, blood and urine routine should be checked regularly.
4, treatment of renal lesions: In addition to actively controlling the blood uric acid level, it is important to alkalize the urine and drink more and urinate more. For gouty nephropathy, when using diuretics, thiazide diuretics, tachyphylaxis and diuretic acid, which affect uric acid excretion, should be avoided, and spironolactone (Amphotericin) and others can be chosen. The carbonic anhydrase inhibitor acetazolamide, which has both diuretic and alkalizing effects on urine, can also be used. Angiotensin-converting enzyme inhibitors can be used to lower blood pressure, and beta-blockers and calcium antagonists, which reduce renal blood flow, should be avoided. For uric acid urinary tract stones, most of them can be dissolved and excreted by themselves, while large and fixed ones can be treated by extracorporeal lithotripsy or surgery. For acute uric acid nephropathy, in addition to the use of allopurinol to actively reduce blood uric acid, it should be treated as acute renal failure. For chronic renal insufficiency, kidney transplantation is possible if necessary.
5. Treatment of asymptomatic hyperuricemia: For people with blood uric acid level below 535μmol/L (9.0mg/dl) and no family history of gout, generally no medication is needed, but diet should be controlled, causative factors should be avoided, and close follow-up should be performed. Instead, uric acid-lowering drugs should be used. In case of concomitant hypertension, diabetes, hyperlipidemia, cardiovascular disease, etc., blood uric acid should be lowered appropriately while treating the concomitant disease.
Prognosis]
If early diagnosis is made and medical advice is followed, modern treatment methods can enable most patients to lead a normal life. In late stage patients, after treatment, gout stones can be dissolved, joint function can be improved, and renal dysfunction can also be improved; patients with first symptoms of gout before the age of 30 are in serious condition. About 20% of gout patients develop uric acid or calcium oxalate stones. Complications include urinary tract obstruction and infection with secondary renal tubular interstitial lesions. Combined hypertension, diabetes mellitus or other renal disease can further lead to impaired urate excretion if left untreated, which not only accelerates the pathological process within the joint, but also further deteriorates renal function to a life-threatening degree.