Overview.
Gout is a heterogeneous group of diseases with impaired purine metabolism and reduced uric acid excretion, caused by hereditary and/or acquired. The main manifestations are hyperuricemia and urate crystallization and deposition resulting in acute arthritis, gout stones, interstitial nephritis, and in severe cases, joint deformity and functional impairment. It is often accompanied by uric acid urinary tract stones. Its prevalence is gradually increasing with the change of lifestyle and the improvement of economic level.
Classification of gout
I. Primary gout
Primary gout is associated with genetic factors, and more and more studies show that primary gout is closely related to obesity, primary hypertension, dyslipidemia, diabetes, and insulin resistance. The main genetic modalities are.
1. idiopathic (cause unknown) molecular defects leading to reduced uric acid excretion, accounting for 80% of primary gout
–The second is excessive uric acid production, which accounts for 10%-20% of primary gout.
2. Enzyme and metabolic defects account for only 1% of primary gout.
Second, secondary gout
Mainly due to kidney disease, blood disease and other diseases, or drugs, high purine food and other causes.
1, enzyme and metabolic defects: myogenic hyperuricemia, Lesch-Nyhan syndrome, PRS hyperactivity, VON Gierke disease, APRT deficiency.
2, Excessive cell destruction/hemolysis, burns, trauma, chemotherapy, radiotherapy, excessive exercise.
3.Cell proliferation: leukemia, lymphoma, myeloma, erythroblastosis.
4, Dietary factors: High purine diet, excessive alcohol consumption.
5.Reduced renal clearance: renal failure, ketoacidosis, gestational hypertensive syndrome, drugs, toxins.
6, Decreased extracellular fluid volume : dehydration, uremia.
Pathogenesis of gout
The occurrence of gout should depend on the concentration of blood uric acid and its solubility in body fluids.
I. Mechanism of hyperuricemia
The balance of blood uric acid depends on the absorption and production versus breakdown and excretion of purines.
1. Absorption: 20% of uric acid in the body comes from the intake of purine-rich foods, and excessive intake can induce gout attacks, but is not the cause of hyperuricemia.
2, decomposition: uric acid is the end product of purine metabolism, about 1/3 of uric acid in normal people is processed by bacterial degradation in the intestine, about 2/3 is excreted by the renal prototype, humans lack uric acid enzymes, so uric acid decomposition is reduced as a mechanism of hyperuricemia has been excluded.
3.Production: 80% of uric acid in the body comes from purine biosynthesis in the body. There are three types of purine nucleotides involved in uric acid metabolism: hypoxanthine nucleotide, adenine nucleotide and guanine nucleotide. Nucleotides are produced in two ways: mainly from amino acids, phosphoribose and other small molecules of non-purine based precursors, which are synthesized in a series of steps; the other way is from the breakdown of nucleic acids, which then produce uric acid step by step. In the process of purine metabolism, there are enzymes involved in the regulation of each link, and once the regulation of enzymes is abnormal, the blood uric acid can be increased or decreased, among which the main ones that cause increased uric acid production are PRS hyperactivity, HGPRT deficiency, etc.
4, excretion: in primary gout, 80% to 90% of the pathogenesis of the direct mechanism is the renal tubular clearance of uric acid salts decreased, the main link to the increase in blood uric acid is believed to be a decrease in renal tubular secretion, including reabsorption is also elevated. Decreased uric acid excretion is often accompanied by increased production.
Mechanism of gout
Gout refers to reactive arthritis or/and gout stone disease caused by uric acid crystallization and deposition. Uric acid is supersaturated in body fluids. The normal range of blood uric acid has a certain span, and generally the blood uric acid concentration that leads to supersaturation is more than 7.0 mg/d1. There are some factors that also affect the solubility of uric acid, such as estrogen, temperature, H+ concentration, etc. can promote uric acid free. In hyperuricemia, even in combination with uric acid stones, it is not called gout. Gout occurs in only 10%-20% of cases of hyperuricemia.
Clinical features of gout
Long-term history of hyperuricemia, mostly in middle-aged and elderly men with obesity and post-menopausal women, 5% to 25% may have a family history of gout.
I. Acute arthritis
Acute arthritis is the first symptom of gout, which is an inflammatory reaction caused by urate crystallization and deposition.
The onset of acute arthritis is rapid, typically starting at midnight, with severe pain and waking up. 90% of the joints are single, occasionally bilateral or multiple joints are involved at the same time or successively, showing redness, swelling, heat and pain, and there may be joint cavity effusion, which may also be accompanied by fever, leukocytosis and other systemic symptoms. The attacks are often self-limiting and resolve spontaneously within hours, days, or weeks, with local flaking and pruritus characteristic of the disease. The remission period can last for months, years or even a lifetime. However, most of the attacks are recurrent, even to the stage of chronic arthritis. In some patients, there is no remission period until the chronic arthritis stage. The pain is usually pronounced, but a few have mild symptoms. Alcohol consumption, high protein diet and foot sprains are important triggers, as well as wearing tight shoes, walking more often, cold, strain, infection and surgery are also common triggers.
The source of uric acid crystals: (1) supersaturated uric acid is released into the joint fluid, and the solubility of sodium urate is 380 umol/L at pH 7.4 and temperature 37.C. High blood uric acid reduces the binding of plasma albumin and globulin, and the local pH and temperature of the joint are lowered, so uric acid crystals precipitate out. (2) Microscopic crystals of gout on the synovial membrane of the joint are shed. The crystals that precipitate activate Hageman factor, 5-hydroxytryptamine, angiotensin, bradykinin, arachidonic acid and the complement system; they can also chemotacticize leukocytes to release leukotriene B4 and glycoprotein chemotactic factors; monocytes can also release interleukin 1 and other inflammatory factors after stimulation to trigger arthritis attacks.
Second, gout stone and chronic arthritis
Gout stone is a chronic foreign body-like reaction caused by the precipitation of fine needle-like crystals of monosodium urate, surrounded by monocytes, epithelial cells, and giant cells to form foreign body nodules, causing a mild chronic inflammatory reaction. Gout stones can involve any part of the body except the central nervous system, most commonly in and near the joints and the otoconia. They appear as yellowish-white elevations of varying sizes, as small as sesame seeds or as large as eggs; they are soft at first and become hard as stones as fibers proliferate, which is characteristic of gout damage. The nodules are easy to wear and tear near the joints, and the nodules make the epidermis thin, easy to break into fistulas, with white paste discharge, the tissue around the fistula is chronic granuloma is not easy to heal, but rarely secondary infection, poor recoverability. The subcutaneous tissue, synovial bursa, cartilage and bone are then injured, causing tissue fracture and fibrous degeneration, with cartilage and bone destruction being the most significant, involving more joints, even to the spine, jaw and other joints, with cartilage showing degenerative changes, formation of vascular opacities, bursal thickening, bone erosion defects and even fractures, coupled with increased gout stones, resulting in joint stiffness, breakdown and deformity.
III. Gouty nephropathy
The characteristic histological manifestation of gouty nephropathy is the presence of urate crystals in the renal medulla or papillae surrounded by round cells and giant cell reactions in a chronic interstitial inflammatory process leading to tubular deformation, epithelial cell necrosis, atrophy, fibrosis, sclerosis, and tubular occlusion, which in turn involves the glomerular vascular bed.
Clinical manifestations include proteinuria, hematuria, isotonic urine, and then hypertension, azotemia, and other manifestations of renal insufficiency. Gout patients die from uremia in 17-25% of cases, but it is rarely caused by gout alone and is often associated with a combination of factors such as advanced age, hypertension, atherosclerosis, renal calculi or infection.
Acute obstructive nephropathy, also known as hyperuricemic nephropathy, is mainly seen in patients with acute and marked increase in blood uric acid due to radiotherapy and chemotherapy, resulting in acute, massive and extensive blockage of uric acid crystals in the renal tubules – acute renal failure. Pathological studies have confirmed that 90% to 100% of patients with gout have kidney damage.
IV. Uric acid urinary tract stones
Stones can appear during the period of hyperuricemia, accounting for 40% of hyperuricemia and 25% of gout patients, which is 200 times higher than the general population, and 10% of stones. The incidence is positively correlated with the blood uric acid level and uric acid excretion, and the incidence of uric acid urinary stones reaches 50% when the blood uric acid is 713.5 μmol/L and the 24-hour excretion exceeds 1100 mg. Most of them are pure uric acid stones, characterized by non-visible X-rays, but some of them are mixed with calcium oxalate and calcium phosphate, which can be visible on X-rays. Sediment-like stones are often asymptomatic, while larger ones have renal colic and hematuria. Among the causes of stones, urinary pH, uric acid concentration, possible utilization of stone matrix, and the level of soluble substances in the urine are also included, especially urinary pH, when pH 8.0 uric acid solubility increases 100 times.
V. Gout and metabolic syndrome
Metabolic syndrome is often accompanied by gout, characterized by obesity, primary hypertension, hyperlipidemia, type 2 diabetes, hypercoagulability and hyperinsulinemia, and accounts for the majority of obese middle-aged and elderly people, with a trend of younger onset in recent years.
Laboratory and other tests
I. Blood uric acid measurement: using serum specimens, uric acid enzyme method, the normal value of 150-380μmol/L for men and 100-300μmol/L for women. generally men >420μmol/L and women >μ350mol/L can determine hyperuricemia. Due to the existence of fluctuations, repeated monitoring should be performed. Each clinical laboratory has different criteria.
II. Measurement of uric acid: Hyperuricemia can be divided into four types: excessive production type, reduced excretion type, mixed type, and normal type. After 5 days of purine restricted diet, the daily uric acid excretion still exceeds 600mg, which can be considered as increased uric acid production.
Bursal fluid examination: In acute arthritis, joint cavity puncture is performed and bursal fluid is extracted for examination, and under the rotating light microscope, needle-shaped uric acid crystals with double refraction phenomenon are seen in leukocytes. The leukocytes, especially the lobulated nuclei, were also found to be increased.
IV. Gout nodule content examination: Specimens were taken from the nodule self-ruptured material or punctured nodule content V. X-ray examination: Non-characteristic soft tissue swelling was seen in the acute arthritis phase; in the chronic phase or after repeated attacks, cartilage margin destruction, joint surface irregularity, cartilage surface, intraosseous, and lumen were seen, cartilage surface, intraosseous, and lumen were seen with gout stone deposition, and hyperplastic reaction was seen on the bone edge, etc. Non-specific manifestations; in typical cases, due to the erosion of uric acid salt into the bone, it shows round or uneven chisel-like translucent defects, which are the X-ray characteristics of gout.
Arthroscopy: During gout attack, tiny nodules are often seen on the synovial membrane, and when the joint cavity is flushed, some of the crystals can be seen to fall off into the joint cavity.
X-ray dual-energy bone density examination: When there is no change in X-ray examination, the decrease in bone density of the injured joint can be detected early.
Ultrasonography: Uric acid urinary tract stones do not show up on X-ray, but ultrasonography can show up. Both X-ray and ultrasonography can reveal mixed type stones.
Diagnosis
1, combined with family history, clinical manifestations of metabolic syndrome, middle-aged and elderly males with onset triggers, sudden midnight arthritis attack or the appearance of uric acid stones, and increased blood uric acid level, the diagnosis of gout can be considered.
2. Diagnosis can be assisted by joint cavity aspiration, gout stone biopsy, X-ray examination, arthroscopy, etc. 3. Diagnostic treatment with colchicine is available for those who are difficult to diagnose, and has characteristic diagnostic value if the treatment is rapidly effective.
Differential diagnosis
Some cases have atypical performance and need to be differentiated from other diseases.
1, acute arthritis: ① rheumatoid arthritis: mostly seen in adolescents, mainly knee arthritis, often with annular erythema, etc.; ② rheumatoid arthritis: mostly seen in young and middle-aged women, mostly small joints, pyknotic swelling, high rheumatoid factor titer; ③ traumatic arthritis: because gout is often attacked after trauma, it is easy to misdiagnose, and it is important that the gout condition and the degree of trauma are not parallel; ④ septic arthritis: systemic (4) septic arthritis: severe symptoms of systemic toxicity without uric acid crystals in the bursal fluid; (5) pseudoarthritis: rare, elderly knee arthritis, calcium pyrophosphate crystals can be seen in the bursal fluid.
2, urinary tract stones: calcium oxalate, calcium phosphate, calcium carbonate stones x-ray visualization, easily confused with mixed uric acid stones, but gouty stones have hyperuricemia and corresponding gout manifestations. Cystine stones do not show up on X-ray, but the blood uric acid is not high.
3, chronic arthritis ① rheumatoid arthritis: chronic stiff deformity of the joint, mostly in young and middle-aged women, blood uric acid does not increase, X-ray lack of chisel-like characteristic defects; ② psoriatic arthritis: about 20% with hyperuricemia, showing asymmetric toe (finger) end joint destruction and bone resorption, X-ray end toe (finger) pencil cap; ③ bone tumor: multiple chisel-like destruction resulting in fracture, deformity and misdiagnosed as Bone tumor.
Treatment
The principle of treatment is early, rapid and effective pain relief, complete termination of acute arthritis and prevention of chronic arthritis. Bed rest should be provided and the affected joint should be placed in the most comfortable position.
I. Acute treatment
Colchicine: It can reduce or terminate chemotactic factors secreted by leukocytes and synovial endothelial cells that phagocytose uric acid salts. Anti-inflammatory and analgesic effects, general usage: ① oral method: 0.5mg/h or lmg/2h, total 4-8mg a day for 24-48 hours, or stop using before the appearance of gastrointestinal symptoms; ② intravenous method: can reduce gastrointestinal reactions. Generally 1~2mg dissolved in saline 20ml, injected slowly for 5-10 minutes, can be injected again for 4-5 hours, total dose not more than 4mg. do not leak! It can cause tissue necrosis. 90% or more cases can terminate the attack. Note: Colchicine has great side effects and toxicity, nausea and vomiting, diarrhea, liver cell injury, bone marrow suppression, hair loss, respiratory depression, etc. Therefore, those with bone marrow suppression, hepatic and renal insufficiency, and leukopenia are prohibited, and those whose treatment is ineffective should not be used again, and should be replaced by NSAIDs.
2. NSAIDs: Indomethacin (anti-inflammatory pain) 25-50mg once, 3 times a day; diclofenac, ibuprofen, ketoprofen, aminoprofen, acemetacin, nimesulide, sulindac, naproxen, meloxicam, piroxicam and other NSAIDs can be used as appropriate, and the dosage should be reduced after the symptoms are controlled. It should be noted that non-steroidal anti-inflammatory drugs also have more digestive system, blood system, kidney and other side effects.
3, glucocorticoid therapy: when the above two types of drugs are ineffective or contraindicated, prednisone 30mg/day.
Generally relieved in 24 to 36 hours. Glucocorticosteroids also have obvious side effects and need to follow medical advice when contraindicated.
4.Promote uric acid excretion and inhibit uric acid synthesis during acute attack can be suspended.
II. Intermittent and chronic treatment
Control the blood uric acid at normal level, prevent and protect the function of damaged organs.
1.Promote uric acid excretion drugs: Decreased uric acid excretion is the main cause of primary gout, this drug is suitable for the period of hyperuricemia and inter-episode and chronic period. When the endogenous creatinine clearance rate of 3.57 mmol (600 mg) or more should not be used. It mainly inhibits the reabsorption of renal tubules. It can be used continuously for 12 to 18 months until uric acid is stable.
Commonly used drugs include: ①Probenzenesulfonamide (carbenzene sulfonamide), 0.25g twice a day for the first time, increasing to 0.5g three times a day within two weeks, with a maximum amount of 2g a day; ②Sulfinpyrazone (benzosulfone), which is stronger than probenzene sulfonamide, 50mg twice a day, gradually increasing to 100mg three times a day; ③Benzbromarone, which is stronger, 25-100mg once a day. Side effects such as rash, fever, gastrointestinal irritation and acute attack are often observed. It is necessary to drink more water and take alkaline drugs such as sodium bicarbonate 3-6g per day during the medication.
2. Inhibition of uric acid synthesis: The mechanism is to inhibit xanthine oxidase and block the conversion of xanthine into uric acid. It is suitable for those who produce too much uric acid or those who are not suitable to use drugs that promote uric acid excretion. Allopurinol: 0.1g, 3 times a day, gradually increasing to 0.2g, 3 times a day; also 0.3g, once a day. It can be used in combination with uric acid excretory drugs for stronger effects, or alone. Side effects include gastrointestinal irritation, skin rash, fever, liver damage, bone marrow suppression, etc. For those with renal insufficiency, it is appropriate to reduce the application by half.
3, dysfunctional people: protection of renal function, joint body therapy, pick out larger gout stones, etc. For acute renal failure, acetazolamide 0.5g should be used first, then 0.25g three times a day, and a large amount of intravenous rehydration and 1.25% sodium bicarbonate solution should be given, while 60-100mg of furosemide should be injected intravenously, so that water can be excreted rapidly and the urine flow can be increased. Allopurinol, a drug that inhibits uric acid synthesis, was used. Hemodialysis is feasible if renal failure is not relieved by the above treatment.
Prevention
Primary gout is a chronic, lifelong disease that cannot be cured at present.
1. Prevention and control objectives.
①Control hyperuricemia and prevent the occurrence of supersaturated urate deposits.
(2) Rapidly terminate acute arthritic attacks.
③ deal with gout stone disease, treatment of the original disease, improve the quality of life.
2.Preventive measures.
①Examine suspected patients and their families for early detection of hyperuricemia.
②Reduce exogenous purine sources and avoid diets with high purine content such as animal offal, fish, shrimp, clams, crabs and other seafood, meat, soy products, etc.
③Adjust the diet structure, actively reduce body weight, control protein diet at lg/kg per day, carbohydrates account for 50%-60% of total calories, and eat less candy, etc.
④Increase uric acid excretion: drink more water, do not use drugs that inhibit uric acid excretion, diuretics, aspirin, etc. ⑤ Avoid triggers that promote the formation of urate crystals: get cold, overwork, stress, wear comfortable shoes, don’t make joints injured, quit drinking, take alkaline drugs, such as adding acetazolamide 0.25g at night to keep urine alkaline and prevent stone formation.
(6) In case of hyperuricemia without gout, use uric acid synthesis inhibitors or/and uric acid excretion promoters as appropriate according to the type of occurrence.