Violation of purine metabolism symptoms in adults. Purine metabolism disorders and gouty nephropathy. Which doctors should I contact if a purine metabolism disorder occurs?

Along with other pathologies, a violation purine metabolism is also considered a serious disease, the treatment of which should be given attention. First of all, these are disruptions in the metabolism of useful substances, which provoke the occurrence of other diseases, such as gout, nephropathy or kidney failure.

As a rule, a disorder of purine metabolism occurs in children, but adults are also susceptible to this pathology. Only usually patients in adulthood are faced with a number of concomitant diseases and complications.

General information

Violation of purine metabolism according to ICD-10 has code E79. Usually this disease is chronic in nature and is directly related to the deposition of acid salts in the tissues of the kidneys and joints. Symptoms of purine metabolism disorders are quite specific and manifest themselves as repeated exacerbations of arthritis, accompanied by pain.

An undetected and untreated problem in time can lead to more serious consequences: for example, the development of urolithiasis and kidney failure. All therapeutic measures in such a situation are usually aimed at relieving unpleasant symptoms, reducing the severity of the clinical picture, preventing the development of complications and normalizing the metabolism of useful substances.

Causes of pathology

A prerequisite for the development of the disease is the excessive formation of purine bases or their too slow excretion with uric acid.

The primary form of the pathology is explained by hereditary predisposition. But the secondary type of the disease may be associated with regular use of diuretics, anti-inflammatory drugs and other medications.

Violations of purine metabolism provoke:

• alcohol;
• severe hypothermia;
• some pharmaceuticals;
• products containing relevant formations;
• pathology infectious nature;
• psycho-emotional and physical stress.

Symptoms

Signs of purine metabolism disorders resemble typical manifestations of metabolic failures. The pathology is characterized by an increased level of creatinine kinase, which appears in almost all patients. Other nonspecific signs of the disease can be detected using an electromyographic examination.

In patients with disorders of purine metabolism, extremely low production of ammonia is observed, due to which performance is significantly reduced and appetite is almost completely absent. Patients feel general malaise, lethargy, and depression. In some cases, pronounced weakness develops.

Children who suffer from disorders of purine metabolism for a long time often remain mentally underdeveloped and have an increased tendency to autism. In more rare cases, small and adult patients experience seizures resembling epileptic seizures, as well as convulsions. Among other things, the psychomotor development of a sick person slows down or stops altogether.

Peculiarities

The most striking disorders of purine metabolism include excessive formation and further accumulation uric acid, which is observed in gout and Lesch-Nyhan syndrome. The latter lies in the hereditary deficiency of a certain enzyme, which leads to the non-use of re-released purines. As a result, they oxidize, transforming into uric acid.

Diagnostics

Detection of the disease is extremely difficult and does not always give an accurate result, since this pathology has many symptoms similar to other disorders in homeostasis. However, with long-term monitoring of the patient’s condition and his tests in general outline, it is quite possible to detect disruptions in purine metabolism and the reasons for its occurrence.

The diagnosis can be made based, first of all, on the complete absence of indicators of the functioning of renal enzymes, active substances of the liver and skeletal muscles. Using laboratory tests, partial deficiency can be detected in lymphocytes and fibroblasts.

Special treatment that would be aimed at eliminating enzyme dysfunction has not yet been developed, so you can only rely on complex therapy.

Treatment

Disorders of purine metabolism require complex treatment, which is based primarily on a strict diet, including foods low in uric acid, and drug therapy.

Pharmacological methods include several stages:

• balance and normalization of metabolic processes with the help of vitaminization;
• establishing metabolic acidosis and controlling the acidic environment in the urine;
• establishment and constant maintenance of normal levels of hyperlipidemia;
• control and normalization of the patient’s blood pressure during the day;
• treatment of possible complications of the pathology.

Treatment of consequences

Gout is a disorder of purine metabolism that was not diagnosed and treated in time. These diseases are very closely related to each other. That is why the signs and treatment of gout are not much different from those with metabolic failures. In general, the treatment of this pathology comes down to the correction of purine metabolism. To do this, the patient is recommended:

• limit physical activity during exacerbations;
• following a certain diet;
• drinking regimen, including 2 liters of water daily;
• the use of local compresses using "Dimexide";
• use of prescribed doses of non-steroidal anti-inflammatory drugs.

Treatment of purine metabolism disorders can be carried out as follows: inpatient conditions, and at home. However, the latter option is permissible only after consultation with a specialist and confirmation of the diagnosis.

Drug therapy

Basic treatment is based on the long-term use of drugs that normalize the amount of uric acid in the blood. Medicines can only be used during remission. Depending on the effect, there are several types of recommended drugs:

• agents that reduce the production of uric acid, for example, Allopurinol;
• medications containing etebenecid increase the rate of elimination of uric acid from the body;
• mixed-action drugs.

Long-term drug therapy is advisable for frequent attacks, severe clinical picture of the disease, formation of tophi and kidney injury.

During periods of remission, patients are also shown a variety of physiotherapeutic procedures: massage, paraffin baths, ultrasound.

In almost all treatment regimens for pathology, doctors mention adherence to a certain diet. A special diet helps the patient effectively eliminate the negative consequences of metabolic disorders. Usually in the role of the first complications, which are effectively dealt with balanced diet, there is a disorder in fat metabolism. Against the background of this pathology, the patient rapidly gains weight, and sometimes faces atherosclerosis, coronary heart disease, and a persistent increase in blood pressure.

In all the situations described, specialists prescribe diets to patients that limit the amount or completely eliminate foods rich in purines. These include: mushrooms, meat, legumes, fish. In addition, patients are shown fasting days with a vegetable, dairy or fruit menu.

It is worth saying that the diet for purine metabolism disorders should be used for quite a long time. The patient's diet includes split meals 4-5 times throughout the day.

The menu also excludes purines and has certain restrictions regarding salt, proteins, fats and carbohydrates. The energy value of the daily diet should range between 2700-2800 calories. The daily menu provides for the consumption of 80 g of protein, 90 g of fat, 400 g of carbohydrates.

• lean meats and fish;
• dairy components;
• bread made from first grade flour;
• all kinds of cereals;
• vegetables and fruits in any form.

Should be excluded:

• fatty types of fish and meat;
• raspberries;
• strong tea and coffee;
• chocolate;
• cocoa powder;
• legumes;
• cranberries;
• sorrel.

A variety of cooking fats are also prohibited.

By following a properly selected diet and other components of complex treatment, the patient feels significant relief in just a few weeks.

The most common disorders of purine metabolism are hyperuricemia and hyperuricosuria. Hyperuricosuria, as a rule, is secondary to hyperuricemia and is a consequence of the kidneys removing excess amounts of urate present in the blood plasma.

Their prevalence, according to various authors, ranges from 5 to 24%. They are detected with greater frequency in men and in the postmenopausal period - in women.

Hyperuricemia is divided into primary (there is no previous predisposing pathology) and secondary (develops as a complication of an existing pathological condition), as well as hyperproduction (metabolic), in which the synthesis of purines is enhanced, hypoexcretion (renal), in which renal elimination of urates is reduced, and mixed.

The development of primary hyperproduction hyperuricemia (HU) can be caused by various enzyme defects: deficiency of glutaminase, deficiency of a specific enzyme - hypoxanthine-guanine-phosphoribosyl-transferrase, hypoproduction of uricase, increased activity of phosphoribosyl-pyrophosphate synthetase, hyperactivity of xanthine oxidase. High levels of uric acid are also observed in some hereditary diseases - Lesch-Nyhan syndrome, glycogenosis type I (Gierke's disease). Environmental factors also play a great role in the development of disease manifestations, and above all physical activity and the nature of nutrition.

Secondary hyperproduction GU develops in all diseases accompanied by increased metabolism or degradation of nucleoproteins. It is also characteristic of conditions associated with tissue hypoxia and a decrease in the level of ATP in tissues, heavy smoking, chronic respiratory failure, and alcoholism (Table 8.9).

Primary hypoexcretionary HU is caused by specific renal hereditary defects in urate transport. It is observed in familial cases of urate nephropathy or juvenile gout. The disease usually debuts at a young age with symptoms of articular gout, against the background of which a sharply reduced sUA clearance and low fractional excretion are found.

Secondary hypoexcretionary TU is observed in various diseases and conditions of the kidneys, accompanied by a decrease in the functioning renal mass, a decrease in glomerular filtration and/or a violation of the tubular transport of Urates (Table 8.9). This occurs with chronic renal failure, dehydration with diabetes insipidus and inadequate use of diuretics, with fasting, diabetic ketoacidosis, acute alcohol intoxication, as well as with long-term use of salicylates even in low doses of ethambutol and nicotinic acid.

Mixed hyperuricemia usually develops in an advanced process, when uric acid accumulates both as a result of increased synthesis and as a result of reduced excretion by damaged kidneys.

Before considering the features of the pathogenesis of disorders of purine metabolism, we highlight the main points of the physiology and pathology of UA metabolism (modern views on this problem were most fully presented in the work of L.A. Nikitina):

Uric acid is the final product catabolism of purine nucleotides that are part of nucleic acids (DNA, RNA), high-energy compounds (ATP, ADP, GDP, GMP) and some vitamins;

In the human body, it is formed in all tissues, mainly in the liver;

Uric acid is a weak keto acid. In the extracellular fluid it is predominantly in a dissociated state with a predominance of monosodium urate;

The solubility of uric acid compounds increases with increasing pH of the medium and decreases with its decrease, and also if the urate concentration exceeds 0.66 mmol/l. This plays a decisive role in the formation of urate crystals in tissues due to disorders of purine metabolism;

On average, about 750 mg is formed and released per day (approximately 10 mg/kg BW). At the same time, 75-80% of it is excreted by the kidneys, the rest is excreted mainly through the intestines, where it is broken down under the action of bacterial uricolysis to CO2 and 1CN3. With dysbacteriosis, the excretion of uric acid through the intestines sharply decreases;

The modern scheme for the excretion of uric acid in urine includes 4 stages: 1) 100% filtration of blood plasma urates through the glomerular membrane; 2) presecretory reabsorption of 98-99% of urates in the initial segment of the proximal tubule; 3) massive secretion (40-50% of the concentration in the blood plasma) of urates on average and partially in the initial segment of the proximal tubule; 4) postsecretory reabsorption of 78-92% of incoming urates in the final segment of the proximal tubule;

LA competes with organic acids for secretion from the blood into the lumen of the tubule;

The level of uricemia in men is on average 0.06 mmol/l higher than in women and increases with age. After 50 years, gender differences in UA content are smoothed out;

U healthy person The metabolic pool of uric acid in the body is about 1-1.2 g. In case of disorders of purine metabolism, it can increase to 15-35 g.

With excess uric acid production, the kidneys correspondingly increase the excretion of urate in the urine (compensatory hyperuricosuria), maintaining normouricemia until, due to specific urate damage, the kidneys begin to lose this ability, which ultimately leads to hyperuricemia. Kidney damage gradually progresses to the development of chronic renal failure.

Clinically, hyperuricemia can manifest itself as gout with tophi and gouty arthritis, hyperuricosuria - gouty nephroplasty and urolithiasis. These diseases are often staged manifestations of the same pathological process.

The classification of gout is based on different types of hyperuricemia. According to etiology, it is divided into primary and

secondary, and according to pathogenesis - metabolic (overproduction) and renal (hypoexcretion). Clinical and laboratory features of various types of gout are presented in table. 8.10.

The complete evolution of gout goes through four stages: asymptomatic hyperuricemia, acute gouty arthritis, intercritical period and chronic gouty urate deposits in the joints. Nephrolithiasis can develop at any stage of gout development, except the first. Among the articular variants of gout, according to the course of the disease, there are: acute gouty arthritis, intermittent arthritis and chronic arthritis with the formation of paraarticular tophi.

Asymptomatic hyperuricemia is a premorbid condition. Moreover, such hyperuricemia can be observed in patients throughout their lives and not manifest any clinical symptoms. On the other hand, this kind of thesaurismosis is a serious predisposing factor to the development of both the articular form of gout and uric acid urolithiasis.

The typical course of gout is characterized by the periodic development of extremely acute arthritis with the typical symptoms of “excruciating joint attacks.” In more than 30-40% of patients, arthritis first affects the metatarsophalangeal joint of the first toe. As the disease progresses, more and more joints are gradually involved in the process. In the chronic stage, functional damage to the joints outside the articular attack persists and is associated with deformation articular surfaces, and with the deposition of uric acid crystals in the periarticular tissues with the formation of tophi. Quite typical is the formation of tophi on the ears and intertendon spaces. In addition, uric acid crystals are often deposited in the kidneys and skin.

The diagnostic significance of various symptoms of gout can be formalized (Table 8.11).

Uric acid, which is formed in excess due to a violation of purine metabolism, is effectively removed from the body by healthy kidneys. With significant hyperuricemia, urate crystals, penetrating into the tissues of the joints, tubules and interstitial tissue of the kidney, cause damage there, in response to which a cellular inflammatory reaction develops. Rushing towards damaged tissue polymononuclear phagocytes realize their function by phagocytosing MK crystals and “fragments” of tissues. As a result of the interaction of phagocytes, primarily macrophages, T- and B-lymphocytes, antibodies are produced, which, when combined with tissue antigens, form immune complexes that trigger a cascade of immunoinflammatory reactions.

Thus, an imbalance in the metabolism of purines in patients with gout is accompanied by changes in the immune system, in particular, as a result of the inferiority of the cellular genome with disturbances at the DNA level in T-lymphocytes, and the detection of high titers of antibodies to the DNA of kidney tissue. Considering that a complete pathway of purine metabolism is necessary to maintain normal reactions of humoral and cellular immunity, a number of authors come to the conclusion that disturbances in the immune response in patients with gout can be both primary and secondary. Primary damage to the immune system develops as a result of a violation of purine metabolism in immunocompetent cells, and secondary disorders immune status- due to prolonged exposure to hyperuricemia and/or chronic autoimmune inflammation.

Hyperuricemia leads to an increase in the content of uric acid in the synovial fluid, its precipitation in the form of needle-shaped crystals with subsequent penetration into the cartilage and synovium. Through cartilage defects, uric acid penetrates to the subchondral bone, where tophi are also formed, and destruction of the bone substance occurs (radiological symptom of a “punch”). At the same time, synovitis occurs in the synovial membrane with hyperemia, proliferation of synoviocytes and lymphoid infiltration. It should be noted that the development of acute gouty arthritis does not occur at the very moment of a sharp increase in the level of uric acid in the blood, but more often at the moment of its decrease after a previous increase.

Damage to various internal organs of varying degrees of severity during chronic course gout was found in more than 2/3 of the patients examined. The kidneys are most often affected. The incidence of kidney damage in gout is high and, according to various authors, ranges from 30 to 65%. Clinically, this can be manifested by uric acid nephropathy and urate nephrolithiasis.

There are acute and chronic uric acid nephropathy

Acute urate nephrottia is characterized by precipitation of uric acid crystals, mainly in the collecting ducts. It is usually transient, tends to recur, and is induced by intercurrent diseases, significant physical activity, thermal procedures, and consumption of foods rich in purines, especially in combination with alcohol. Its most typical manifestation is the occasional appearance of brown urine, sometimes accompanied by an increase in blood pressure. The extreme severity of acute uric acid nephropathy is acute renal failure, which often requires hemodialysis. This type of kidney damage is more typical for secondary disorders of uric acid metabolism, but there is a possibility of its development in primary gout with extreme hyperuricosuria.

Chronic gouty nephropathy can manifest itself in the form of chronic hyperuricosuric persistent obstructive tubular nephropathy, chronic interstitial nephritis and chronic glomerulonephritis. During chronic gouty nephropathy, 3 stages can be distinguished (see Table 8.10). Stage I - hyperuricosuric - is characterized by hyperuricosuria with often normal or slightly elevated levels of uric acid in the blood plasma. Kidney damage is manifested by microalbuminuria and increased N-acetyl-O-glucosaminidase (NAG) activity. // stage - hyperuricemic - characterized by hyperuricemia with normal, slightly increased or decreased daily excretion of uric acid. Kidney damage is manifested by nocturia, decreased relative density of urine, impaired osmoregulatory function, and increased proteinuria. This stage is a reflection of the condition when the kidneys, due to their damage, are not able to compensate for the increased urate load. Stage III - azotemic - is manifested by significant hyperuricemia, low daily excretion of uric acid, an increase in the concentration of plasma creatinine, a decrease in glomerular filtration, and the development of chronic renal failure.

Tubulointerstitial lesions predominate in most cases early stages diseases, glomerular - in the terminal phase of the disease, where pronounced glomerulo- and angiosclerosis is observed.

Chronic renal failure characterized by slow progression, especially with an initial blood creatinine level not exceeding 440 µmol/l (CRF-PA), with adequate control of hyperuricemia. Terminal uremia occurs in 4% of patients. It develops later than in patients with terminal chronic renal failure caused by another pathology. When treated with hemodialysis, typical gouty arthritis persists. Exacerbations often coincide with intensification of hemodialysis and significant dehydration.

Urolithiasis is found in 10-22% of patients with primary gout. In a number of patients, kidney stones develop before the first attack of gouty arthritis. Factors predisposing to the development of nephrolithiasis in gout include persistent acidification of urine, increased uric acid excretion in the urine, and decreased urine output.

In a significant proportion of patients, chronic kidney damage due to gout and hyperuricemia is characterized latent course and the gradual development of renal failure. It is based on chronic inflammatory process with damage to the glomerular apparatus, as well as the interstitium of the kidneys.

Among the mechanisms of the damaging effect of uric acid on the kidneys, the following are currently being discussed: direct nephrotoxic effect, interaction of sodium urate crystals with polymorphonuclear leukocytes, leading to the development of an inflammatory reaction.

One of the clinical important options Kidney damage due to gout can be glomerulonephritis. It is characterized by the predominance of hematuria and steady progression towards chronic renal failure. An essential feature of gouty glomerulonephritis are episodes of reversible deterioration of kidney function caused by transient uric acid blockade of the renal tubules, developing in conditions of dehydration and decreased diuresis. A typical manifestation of glomerulonephritis in gout is a decrease in the ability of the kidneys to osmotic concentration of urine, detected in approximately 1/3 of patients with still preserved nitrogen excretory function of the kidneys. Often, simultaneously with the development of glomerulonephritis, vascular damage occurs at the level of the microvasculature (including in the kidneys). The reason is activation of complement, leukocytes and platelets by uric acid crystals with subsequent damage to the vascular endothelium.

Of particular interest are kidney lesions with so-called “asymptomatic” hyperuricemia. In this case, latent kidney damage develops, which is based on severe morphological changes in the renal tissue in young people with moderate hyperuricemia and normal blood pressure. Morphological changes in this case are reduced to glomerulosclerosis, thickening of the tubular basement membrane, tubular atrophy, sclerosis of the interstitium and blood vessels. Tubular obstruction plays a leading role in the pathogenesis of these lesions.

Among patients with chronic glomerulonephritis, there is a group of people with persistent hyperuricemia and/or hyperuricosuria. A feature of the clinical manifestations of such glomerulonephritis in patients is the predominant prevalence of this condition among men, severe gross hematuria, a decrease in the concentration function of the kidneys up to isosthenuria, which often develops long before azotemia, as well as the possibility of the addition of gouty arthritis several years after the discovery of persistent urinary syndrome. Distinctive feature cellular immunity in such patients is a high (up to 80%) frequency of sensitization to antigens of the epithelium of the brush border of the renal tubules with the simultaneous detection of high titer antibodies in the blood to these antigens. The inclusion of immune mechanisms leads to damage to the glomerular apparatus of the kidney, which a number of researchers explain by the cross-reactive properties of the glomerular and tubular antigen against the background of an autoimmune process.

From this point of view, hyperuricemia and hyperuricosuria can be considered as a possible etiopathogenetic factor in the development and progression of chronic glomerulonephritis.

In addition to hyperuricemia and disorders in the immune system, lipids play an important role in the genesis of gouty nephropathy. Hyperlipidemia is considered as one of the factors in the progression of gouty nephritis and a manifestation of nephrotic syndrome. The frequency and degree of beta-lipoproteinemia and triglyceridemia, increasing as renal failure progresses, confirm this. Lipoproteins are deposited in the glomeruli and renal vessels. All this leads to sclerosis of the glomeruli and shrinkage of the kidneys with the development of arterial hypertension and increasing renal failure. It is believed that the development of hyperlipoproteinemia contributes to

progression of systemic atherosclerotic lesions.

Although the connection between gout and atherosclerosis has been known for a long time, the role of gout as an independent risk factor for atherosclerosis is still being discussed. According to some data, the prevalence of atherosclerosis in patients with gout is 10 times higher than in the general population. In addition to lipid metabolism disorders, gout is characterized by typical changes in the system of regulation of the aggregate state of the blood, which are also characteristic of patients with atherosclerosis.

Yu.A. Pytel et al. found that there is a possible connection between hyperuricemia and hyperglycemia. With hyperuricemia, alloxan, a product of oxidation and breakdown of uric acid, can accumulate in the body. It has been proven that this metabolite can cause necrosis of basophilic insulocytes of pancreatic islets without clear damage to the endocrine part of the gland.

Thus, the pathogenesis of gout is characterized by the closure of a number of “vicious” circles:

The development of primary hyperuricemia leads to toxic damage to the kidneys as the main factor in the progression of gout, up to the development of chronic renal failure, and the excretion of uric acid decreases below normal values ​​already in the very early stages of hyperuricemic nephropathy;

Uric acid and its derivatives, accumulating in tissues, initiate the development of an immunopathological inflammatory reaction with disturbances in the activity of the monocyte-macrophage system and segmented-nuclear leukocytes. Disturbances in the cellular and humoral immunity, aggravating each other, lead to the development of an autoimmune process;

In a significant proportion of patients with gout, along with disturbances in uric acid metabolism, disturbances in carbohydrate and lipid metabolism are noted with a rapidly progressing and torpid course of atherosclerotic vascular lesions and type II diabetes mellitus. These violations have a mutually aggravating effect.

The main cause of death in patients with gout is uremia, as well as heart failure, heart attacks and strokes associated with nephrogenic hypertension and atherosclerosis.

Therapeutic approaches. Treatment of gout is based on a combination of three main components: diet, basic therapy and symptomatic therapy, which are aimed primarily at relieving articular syndrome and reducing hyperuricemia.

Diet. The anti-gout diet (diet No. 6 according to A. Pokrovsky) provides for a sharp limitation in the consumption of foods rich in purines (brains, liver, kidneys, tongue, caviar, herring, canned fish, legumes, mushrooms, cauliflower, spinach, peanuts, coffee, tea, cocoa, chocolate, yeast), and in some cases - oxalic acid, reducing the amount of proteins and lipids consumed, fasting days (dairy, vegetable or fruit) 2 times a week. It is advisable to use alkaline mineral waters.

Basic thearpy. When determining a program of drug therapy for gout with drugs that normalize the metabolism and release of purines, several conditions must be met:

Consideration of the type of purine metabolism disorder; with rare exceptions, start drug treatment should only be done during the interictal period;

Maintaining high daily diuresis (more than 2 liters) and using urine alkalizing agents;

Treatment should be persistent (breaks of more than 2-3 days are not allowed) and long-term (years) subject to a strict nutritional and active physical regimen.

There are several special drugs that can be fundamentally divided into two large groups. The first group of basic therapy drugs consists of drugs that block the synthesis of uric acid - uricodepressors, the second group consists of drugs that enhance the excretion of uric acid - uricosuretics.

Inhibitor of uric acid synthesis - allopurinol (milurit Eg18, allocyme §a\ua1, zyloric ShsPsotc. purinol Bis1\\1§ Meglye, urosin Boebppeger Mapbinspp. sanfipurol §apoy-\Vm1:- gor) - has a specific the ability to inhibit the enzyme xanthine oxidase, which ensures the conversion of hypoxanthine into xanthine and then xanthine into uric acid. It is effective in treating all types of hyperuricemia, however, it is most effective in:

In patients with gout with obvious overproduction of uric acid, nephrolithiasis, renal failure, tophi, and with previously noted ineffectiveness of uricosuretics;

In patients with urolithiasis of any origin with daily excretion of uric acid above 600 mg/day, as well as in patients with uric acid nephropathy or at a high risk of its development.

The initial dose of allopurinol for mild forms of primary gout is 200-300 mg per day - with severe forms can reach 400-600 mg in 2-3 doses. A decrease in the level of uric acid in the blood to normal (0.32 mmol/l) is usually achieved in 2-3 weeks, this determines the transition to maintenance doses of the drug (100-200 mg/day). In patients with hyperuricemia of various origins and impaired partial renal function, the dose of allopurinol should be reduced by 25-30%. In such cases, the combination of allopurinol with uricoeliminators is justified - in the form of allomaron, the tablet of which contains 100 mg of allopurinol and 20 mg of benzobromarone.

The use of uricodepressors and, first of all, allopurinol is quite effective. However, its side effects and toxic effects occur in 5-20% of patients. It should be borne in mind that in approximately 1/4 of patients with gout, liver function is impaired to one degree or another, which requires special caution when prescribing allopurinol. Difficulties in achieving relief of purine metabolism disorders dictated the need to search for new methods for their correction. In this regard, the experience of using purine antagonists is interesting. However, as noted by O.V. Sinyachenko (1990), this treatment method has clear indications and contraindications and cannot be widely used in patients with gout.

Uricouretics reduce plasma uric acid levels by increasing its renal excretion. This is achieved by partially inhibiting the reabsorption of uric acid in the proximal tubule or through other mechanisms. The group of uricosuretic drugs includes probenecid, etebenecid (ethamide), acetylsalicylic acid in large doses, sulfinpyrazone, ketazone, benzbromarone, etc. Indications for their isolated use may include:

Absence of severe gouty nephropathy;

Mixed type of gout with daily urate excretion of less than 3.5 mmol (allopurinol intolerance.

Probenecid is considered the drug of first choice (Benemid). The initial dose is 0.5 g 2 times a day, which is then increased to an effective dose, usually 1.5-2 g per day and maintained at this level until uricemia is normalized. Maintenance dose - 0.5 g 1-2 times a day. In large doses, it increases the excretion of uric acid, blocking tubular readsorption; in small doses, it only blocks tubular secretion. The effect of the drug is blocked by salicylates. For its part, probenecid interferes with the renal excretion of penicillins and indomethacin and the metabolism of heparin, which must be taken into account when using this uricoeliminator against the background of the use of anticoagulants. Less effective is etebenecid (ethamide), which also inhibits the readsorption of uric acid in renal tubules. The usual dose of etamide for adults: 0.35 g 4 times a day, course - 10-12 days; after a week's break the course can be repeated. In acute attacks of gout, etamide is practically ineffective, has no analgesic effect, and the use of NSAIDs is difficult.

Sulfinpyrazone (anthuran Sla) is a derivative of pyrosolidone (butadione). It also does not have a significant analgesic or anti-inflammatory effect, but is an active antiplatelet agent, which allows its use in the recovery period after myocardial infarction. The daily dose of anturan is 400-600 mg in 2-3 doses after meals. It is well absorbed, the duration of action of one dose is 8-12 hours. Once the effect is achieved, switch to a maintenance dose of the drug - 100 mg 2-3 times a day. Another pyrosolidone derivative, ketazone (kebuzone BecNa), on the contrary, has a pronounced anti-inflammatory effect. This allows you to use it during an acute attack of gout in injection form (20% solution 5 ml) 1-2 g per day for 2 days, then 3-4 tablets (0.25 mg each) until signs of arthritis disappear, with switching to 1 tablet as a maintenance dose. With a small volume of urine excreted and renal calculi of any type, these uricosuric drugs are contraindicated.

A promising uricosuric agent is considered to be benzbromarone (desuric Labar, as well as normulat, hipuric), which not only intensively suppresses the reabsorption of urates, but to some extent also blocks the synthesis of purines. In addition, under the influence of benzbromarone, the excretion of purines through the intestines increases. The indication for its use is both primary gout and latent and secondary hyperuricemia. Benzbromarone preparations are prescribed gradually, starting with 50 mg per day; if laboratory monitoring does not achieve a clear decrease in uricemia, switch to an average dose of 100 mg (1 tablet of desuric or normulate). In case of acute attacks of gout, sometimes a short course of high doses is immediately administered - 150-200 mg per day for 3 days, followed by a transition to a maintenance dose of the drug. When pain in the affected joints increases with benzbromarone, NSAIDs are indicated. Gastrointestinal upset (diarrhea) is a fairly rare complication, but it can be reduced by using a micronized form (hipuric), the equipotential tablet of which contains 80 mg of benzbromarone.

Uricouretics are effective in 70-80% of patients. In about 9%, it provokes the formation of kidney stones. The effectiveness of uricosuretics decreases with clear impairment of renal function. When glomerular filtration by creatinine clearance decreases below 30 ml/min, they become completely ineffective.

You can increase the excretion of uric acid with the help of enterosorbents. As XV believed. CoIT (1976), with the help of coal adopted reg 05, it is possible to remove from the body not only creatinine, but also uric acid. According to S. Sporclan et al. , the administration of coke coal at a dose of 20-50 g per day significantly reduced the concentration of uric acid in the blood. Similar data were obtained by M. Max\\e11 et al. (1972). As noted by B.G. Lukichev et al. , during enterosorption using a carbon sorbent, SCN was determined statistically already on the 10th day significant decrease concentrations of blood triglycerides in kidney patients, and by the 30th day, while the trend towards a decrease in triglycerides remained, a decrease in total serum cholesterol was observed. The same authors propose a trial administration of such drugs for a period of 10 days as a test to determine indications for ES in nephropathy. If, after the specified period, a decrease or stabilization of blood creatinine, lipids and other substances characterizing the pathology is recorded, then treatment should be continued. It should be noted that in order to achieve a clear positive clinical and laboratory effect, ES should be carried out persistently and for a long time - at least a month.

Symptomatic treatment of gout includes relief of articular gouty attacks, prevention and treatment of urolithiasis and correction of concomitant metabolic disorders.

The most powerful drug that relieves acute gouty arthritis is colchicine, the mechanism of action of which is to suppress the migration of neutrophils and their phagocytosis of uric acid crystals. However, in some cases, when treating gout with colchicine, complications associated with its toxicity develop. In this case, it is necessary to quickly reduce and/or discontinue the drug intake. It has been found that colchicine is not effective in 25-40% of patients. Symptomatic means of relieving gout attacks include non-steroidal anti-inflammatory drugs of the pyrazolone (butadione, reopirin, ketazone, phenylbutazone, etc.) and indole (indomethacin) series. However, they also have certain side effects and limited effectiveness. Sometimes an acute articular attack can only be stopped with local, intra-articular, or even systemic use of GCS.

A whole group of granular oral medications used to dissolve stones containing uric acid or prevent their formation (Uralit-11, Blemaren, Soluran, Solimok). The basis of these drugs are citric acid salts, which weaken the acidic reaction of urine and thereby prevent the loss of urates in the form of crystals. Some of these drugs can be used to alkalinize urine when using cytostatics and treating porphyria cutanea tarda. In cases with persistent acidic urine reaction (pH less than 5.5) and the presence of stones consisting of a mixture of oxalates and urates, it is preferable to use Magurlit and Oxalite S. To achieve maximum effect, it is desirable that the urine reaction is within the pH range of 6.0-6 ,4. Exceeding this level promotes the formation of phosphate or practically insoluble urate-oxalate stones.

Side effects of drug therapy. Increasingly, there is information about the presence of contraindications to long-term use of uricodepressor and uricosuric drugs, as well as

NSAIDs in patients with gouty nephritis. Thus, long-term use of allopurinol can cause hepatotoxic and nephrotoxic effects, which makes it necessary to reduce the dose of the drug or completely cancel it, and to search for other drugs that can affect purine metabolism. It has been established that the use of etamide and its analogues from the group of uricosuric drugs is contraindicated for urolithiasis, as well as for progression of chronic renal failure. Long-term use of drugs in this group for gouty nephropathy also seems undesirable due to a real increase in the risk of stone formation in the kidneys.

NSAIDs used to treat arthritis and arthralgia in patients with gout often contribute not only to an increase in the concentration of uric acid in the blood, but also to the progression of tubulointerstitial nephritis, one of the most common types of gouty nephropathy. The progression of urinary syndrome, arterial hypertension, and urolithiasis is noted both with irregular use of uricosuric, uricodepressor drugs, uroantiseptics, citrate mixtures, antihypertensive and diuretic drugs, and with regular use of these drugs in the complex therapy of gout with gouty nephropathy.

Consequently, long-term treatment of patients with conventional anti-gout drugs against the background of clear positive dynamics in the joints and reduction of subcutaneous tophi does not prevent the deterioration of kidney function. Moreover, in the presence of signs of established nephropathy, additional drug-induced damage to the interstitium and tubules can significantly accelerate the development of chronic renal failure. The need to search for new treatment methods is especially acute in patients with poor tolerance to traditional drugs or with the development of resistance to them.

Extracorporeal hemocorrection. The first attempt to use extracorporeal hemocorrection in the treatment of patients with gout in the form of hemosorption was made in the late 80s by A.A. Matulis et al. . However, this method was not without its drawbacks; it was often poorly tolerated by such patients and often had complications. We have been studying the effectiveness of using apheresis technology in the complex treatment of gout for a long time.

Based on the results of research and clinical experience, we consider the addition indicated traditional therapy gout with a course of extracorporeal hemocorrection in the following cases:

With the development of resistance to drugs that relieve articular gout attack, or to drugs for the basic therapy of gout;

In case of intolerance or poor tolerance to drugs for basic therapy of gout, or drugs that stop articular attack;

With a steadily progressing course of gout;

In the presence of progression of gouty nephropathy;

In case of severe immunological disorders. Initially, the operation of choice was non-selective plasmapheresis. At the end of the course of treatment, all patients who received PF noted positive clinical dynamics in the form of improved well-being, absence of arthralgia, and increased joint mobility. Nonselective PF significantly reduced the content of CEC in the blood plasma of patients with gouty nephropathy. A tendency towards normalization of the concentration of sialic acids and fibrinogen, a decrease in the platelet content in the general blood test and the relative density of urine below the norm was revealed. However, 1/3 of the patients had poor tolerability to the operation. The disadvantage was the frequent development of the “rebound” phenomenon, which was manifested clinically by a sharp increase in articular syndrome with a simultaneous increase in the blood concentration of uric acid and various inflammatory mediators involved in the pathogenesis and determining the clinical picture of gout. This forced me to stop treatment and return to conventional drug therapy.

Conditionally selective surgery with cryosorbed autoplasma (CSAP) is more effective and rational. The modification of autoplasma is based on the method of cryoprocessing of plasma presented above. It was found that in the treated autoplasma the level of uric acid decreased by an average of 90%, MSM - by 78%, CEC - by 78%, fibrinogen - by 64%, creatinine - by 61%, triglycerides - by 56%, beta-lipid. roteins - by 48%, urea - by 38%, cholesterol - by 37%, 1§C - by 36%, 1§A - by 28%, with a slight elimination of total protein (by 14%) and albumin (by 15% ).

When applied as a course, this method of hemocorrection has a more pronounced detoxification, immunocorrective, rheocorrecting and delipidizing effect and greater selectivity to pathogenicity factors than non-selective PF. In addition to the removal of uric acid during extracorporeal surgery, its excretion by the kidneys increases significantly.

All 173 patients achieved clinical and laboratory remission, which was expressed in relief of arthralgia, disappearance of arthritis symptoms, increased functional ability of joints, improved well-being, and normalization of laboratory and functional parameters. The tolerability of the operations during the course was good, the frequency of the “uricemic rebound” phenomenon decreased significantly, the effect was more pronounced, and the remission was longer. In addition, angina attacks in the presence of concomitant ischemic heart disease were reduced, arterial hypertension was reduced, sensitivity to basic therapy was increased, and the frequency of its side effects was significantly reduced.

Particularly noteworthy is the stability of indicators of renal function (secretory-excretory activity of the tubular apparatus on isotope renography, an increase in the range of relative density of urine in the Zimnitsky test, glomerular filtration and tubular reabsorption) in 26 patients with diagnosed gouty nephropathy, both immediately after the course of operations and six months later after her. This was most noticeable when comparing a group of patients who received complex treatment using a course of CSAP plasma exchanges and conventional pharmacological therapy.

The combination of plasma sorption with CSAP plasma exchange allows the treatment to be optimized and made more rational. The course of hemocorrection in this case consists of 2 plasmapheresis operations with plasma sorption and 2-3 CSAP operations. The volume of exfusion during plasmapheresis is 35-40% of the VCP, the volume of plasma sorption is 1 VCP. Volume replacement and processing of the resulting plasma are carried out in the same way as with QSAP software. The plasma exfused during the first two operations is reinfused into the patient at the 3rd operation. When using this treatment regimen, the efficiency of uric acid removal increases significantly (1.6 times). A positive effect and long-term remission are achieved in 72% of patients with hyperuricemia more than 500 µmol/l, the most resistant to therapy. If therapy is ineffective, it is necessary to consider the advisability of prescribing uricodepressors in parallel with efferent therapy. . The criterion for the sufficiency of a course of surgery is the normalization of uric acid levels.

William N. Kelley, Thomas D. Patella

The term “gout” refers to a group of diseases that, when fully developed, are manifested by: 1) an increase in the level of urate in the serum; 2) repeated attacks of characteristic acute arthritis, in which crystals of monosubstituted sodium urate monohydrate can be detected in leukocytes from the synovial fluid; 3) large deposits of sodium urate monohydrate (tophi), mainly in and around the joints of the limbs, sometimes leading to severe lameness and joint deformities; 4) damage to the kidneys, including interstitial tissues and blood vessels; 5) the formation of kidney stones from uric acid. All these symptoms can occur individually or in various combinations.

Prevalence and epidemiology. An absolute increase in the level of urate in serum is said to exist when it exceeds the solubility limit of monosubstituted sodium urate in this medium. At a temperature of 37°C, a saturated solution of urate in plasma is formed at a concentration of approximately 70 mg/l. A higher level means supersaturation in a physico-chemical sense. Serum urate concentration is relatively elevated when it exceeds the upper limit of an arbitrarily defined normal range, usually calculated as the mean serum urate level plus two standard deviations in a population of healthy individuals grouped by age and sex. According to most studies, the upper limit for men is 70, and for women - 60 mg/l. From an epidemiological point of view, urate concentration c. serum more than 70 mg/l increases the risk of gouty arthritis or nephrolithiasis.

Urate levels are affected by gender and age. Before puberty, serum urate concentration is approximately 36 mg/L in both boys and girls; after puberty, it increases more in boys than in girls. In men, it reaches a plateau after the age of 20 and then remains stable. In women aged 20-50 years, the urate concentration remains at a constant level, but with the onset of menopause it increases and reaches a level typical for men. It is believed that these age- and gender-related variations are associated with differences in the renal clearance of urate, which is obviously influenced by the content of estrogens and androgens. Other physiological parameters such as height, body weight, blood urea nitrogen and creatinine levels are also correlated with serum urate concentration. arterial pressure. Elevated serum urate levels are also associated with other factors, such as high ambient temperature, alcohol consumption, high social status or education.

Hyperuricemia, by one definition or another, is found in 2-18% of the population. In one of the examined groups of hospitalized patients, serum urate concentrations of more than 70 mg/l occurred in 13% of adult men.

The incidence and prevalence of gout is less than hyperuricemia. In most Western countries, the incidence of gout is 0.20-0.35 per 1000 people: this means that it affects 0.13-0.37% of the total population. The prevalence of the disease depends on both the degree of increase in serum urate levels and the duration of this condition. In this regard, gout is mainly a disease of older men. Women account for only up to 5% of cases. In the prepubertal period, children of both sexes rarely become ill. The usual form of the disease only rarely appears before the age of 20 years, and the peak incidence occurs in the fifth 10th year of life.

Inheritance. In the USA, a family history is revealed in 6-18% of cases of gout, and with a systematic survey this figure is already 75%. The exact mode of inheritance is difficult to determine due to the influence of environmental factors on serum urate concentrations. In addition, the identification of several specific causes of gout suggests that it represents a general clinical manifestation heterogeneous group of diseases. Accordingly, it is difficult to analyze the pattern of inheritance of hyperuricemia and gout not only in the population, but also within the same family. Two specific causes of gout - deficiency of hypoxanthine guanine phosphoribosyltransferase and hyperactivity of 5-phosphoribosyl-1-pyrophosphate synthetase - are X-linked. In other families, inheritance follows an autosomal dominant pattern. Even more often, genetic studies indicate multifactorial inheritance of the disease.

Clinical manifestations. The complete natural evolution of gout goes through four stages: asymptomatic hyperuricemia, acute gouty arthritis, intercritical period and chronic gouty joint deposits. Nephrolithiasis can develop at any stage except the first.

Asymptomatic hyperuricemia. This is the stage of the disease in which serum urate levels are elevated but symptoms of arthritis, gouty joint deposits, or uric acid stones are not yet present. In men susceptible to classic gout, hyperuricemia begins during puberty, whereas in women at risk it usually does not appear until menopause. In contrast, with some enzyme defects (see below), hyperuricemia is detected already from the moment of birth. Although asymptomatic hyperuricemia may persist throughout the patient's life without apparent complications, the tendency for it to progress to acute gouty arthritis increases as a function of its level and duration. The risk of nephrolithiasis also increases as serum urate increases and correlates with uric acid excretion. Although hyperuricemia is present in virtually all gout patients, only approximately 5% of individuals with hyperuricemia ever develop the disease.

The stage of asymptomatic hyperuricemia ends with the first attack of gouty arthritis or nephrolithiasis. In most cases, arthritis precedes nephrolithiasis, which develops after 20-30 years of persistent hyperuricemia. However, in 10-40% of patients renal colic occur before the first attack of arthritis.

Acute gouty arthritis. The primary manifestation of acute gout is extremely painful arthritis at first, usually in one of the joints with scanty general symptoms, but later several joints are involved in the process against a background of a feverish state. The percentage of patients in whom gout immediately manifests itself as polyarthritis is not precisely established. According to some authors, it reaches 40%, but most believe that it does not exceed 3-14%. The duration of attacks varies, but is still limited, they are interspersed with asymptomatic periods. In at least half of the cases, the first attack begins in the joint of the metatarsal bone of the first toe. Eventually, 90% of patients experience attacks of acute pain in the joints of the first toe (gout).

Acute gouty arthritis is a disease primarily of the legs. The more distal the location of the lesion, the more typical the attacks. After the first toe, the joints are involved in the process metatarsal bones, ankle, heel bones, knee bones, wrist bones, fingers and elbows. Acute pain attacks in the shoulder and hip joints, joints of the spine, sacroiliac, sternoclavicular and mandibular joints rarely appear, except in persons with a long-term, severe disease. Sometimes gouty bursitis develops, and most often the bursae of the knee and elbow joints are involved in the process. Before the first sharp attack of gout, patients may feel constant pain with exacerbations, but more often the first attack is unexpected and has an “explosive” character. It usually begins at night, and the pain in the inflamed joint is extremely severe. An attack can be triggered by a number of specific reasons, such as trauma, consumption of alcohol and certain medications, errors in diet, or surgery. Within a few hours, the intensity of the pain reaches its peak, accompanied by signs of progressive inflammation. In typical cases, the inflammatory reaction is so pronounced that it suggests purulent arthritis. Systemic manifestations may include fever, leukocytosis, and accelerated erythrocyte sedimentation. It is difficult to add anything to the classic description of the disease given by Syndenham:

“The patient goes to bed and falls asleep in good health. At about two o'clock in the morning he wakes up from acute pain in the first toe, less often in the heel bone, ankle joint or metatarsal bones. The pain is the same as with a dislocation, and there is also the feeling of a cold shower. Then chills and trembling begin, and body temperature rises slightly. The pain, which was moderate at first, becomes increasingly severe. As it worsens, the chills and trembling intensify. After some time, they reach their maximum, spreading to the bones and ligaments of the tarsus and metatarsus. There is a feeling of stretching and tearing of the ligaments: gnawing pain, a feeling of pressure and bursting. Diseased joints become so sensitive that they cannot tolerate the touch of a sheet or shock from the steps of others. The night passes in agony and insomnia, attempts to place the sore leg more comfortably and constant searches for a body position that does not cause pain; throwing is as long as the pain in the affected joint, and intensifies as the pain worsens, so all attempts to change the position of the body and the sore leg are futile.”

The first attack of gout indicates that the concentration of urate in the serum has long been increased to such an extent that large quantities have accumulated in the tissues.

Intercritical period. Gout attacks may last for one or two days or several weeks, but usually resolve spontaneously. There are no consequences, and recovery seems complete. An asymptomatic phase begins, called the intercritical period. During this period, the patient does not make any complaints, which has diagnostic significance. If in approximately 7% of patients the second attack does not occur at all, then in approximately 60% the disease recurs within 1 year. However, the intercritical period can last up to 10 years and end with repeated attacks, each of which becomes increasingly longer, and remissions become less and less complete. With subsequent attacks, several joints are usually involved in the process; the attacks themselves become increasingly severe and prolonged and are accompanied by a feverish state. At this stage, gout can be difficult to differentiate from other types of polyarthritis, such as rheumatoid arthritis. Less commonly, chronic polyarthritis without remission develops immediately after the first attack.

Accumulations of urate and chronic gouty arthritis. In untreated patients, the rate of urate production exceeds the rate of its elimination. As a result, its quantity increases, and eventually in cartilage, synovial membranes, tendons and soft tissues clusters of monosubstituted sodium urate crystals appear. The rate of formation of these accumulations depends on the degree and duration of hyperuricemia and the severity of kidney damage. The classic, but probably not the most common site of accumulation is the helix or antihelix auricle(Fig. 309-1). Gouty deposits are often localized along the ulnar surface of the forearm in the form of protrusions of the bursa elbow joint(Fig. 309-2), along the Achilles tendon and in other areas under pressure. It is interesting that in patients with the most pronounced gouty deposits, the helix and antihelix of the auricle are smoothed.

Gouty deposits are difficult to distinguish from rheumatoid and other types of subcutaneous nodules. They may ulcerate and secerate a whitish viscous liquid rich in monosodium urate crystals. Unlike other subcutaneous nodules, gouty deposits rarely disappear spontaneously, although they may slowly decrease in size with treatment. Detection of monosodium urate crystals in the aspirate (using a polarizing microscope) allows the nodule to be classified as gouty. Gout deposits rarely become infected. In patients with noticeable gouty nodules, acute attacks of arthritis appear to occur less frequently and are less severe than in patients without these deposits. Chronic gouty nodules rarely form before the onset of arthritis attacks.

Rice. 309-1. Gouty plaque in the helix of the auricle next to the ear tubercle.

Rice. 309-2. Protrusion of the elbow joint bursa in a patient with gout. You can also see accumulations of urate in the skin and a slight inflammatory reaction.

Successful treatment reverses the natural evolution of the disease. With the advent of effective antihyperuricemic agents, only a small number of patients develop noticeable gouty deposits with permanent joint damage or other chronic symptoms.

Nephropathy. Some degree of renal dysfunction is observed in almost 90% of patients with gouty arthritis. Before the introduction of chronic hemodialysis, 17-25% of patients with gout died from renal failure. Its initial manifestation may be albumin or isosthenuria. In a patient with severe renal failure, it is sometimes difficult to determine whether it is due to hyperuricemia or whether the hyperuricemia is the result of kidney damage.

Several types of renal parenchymal damage are known. Firstly, this is urate nephropathy, which is considered to be the result of the deposition of monosodium urate crystals in the interstitial tissue of the kidneys, and secondly, obstructive uropathy, caused by the formation of uric acid crystals in the collecting ducts, renal pelvis or ureters, as a result of which the outflow of urine is blocked.

The pathogenesis of urate nephropathy is a subject of intense controversy. Despite the fact that monosodium urate crystals are found in the interstitial tissue of the kidneys of some patients with gout, they are absent in the kidneys of most patients. Conversely, urate deposition in the renal interstitium occurs in the absence of gout, although clinical significance these deposits are unclear. Factors that may contribute to the formation of urate deposits in the kidneys are unknown. In addition, in patients with gout, there was a close correlation between the development of renal pathology and hypertension. It is often unclear whether hypertension causes renal pathology or whether gouty changes in the kidneys cause hypertension.

Acute obstructive uropathy is a severe form of acute renal failure caused by the deposition of uric acid crystals in the collecting ducts and ureters. However, renal failure is more closely correlated with uric acid excretion than with hyperuricemia. Most often, this condition occurs in individuals: 1) with pronounced overproduction of uric acid, especially against the background of leukemia or lymphoma, undergoing intensive chemotherapy; 2) with gout and a sharp increase in uric acid excretion; 3) (possibly) after heavy physical activity, with rhabdomyolysis or seizures. Aciduria promotes the formation of poorly soluble non-ionized uric acid and therefore may increase crystal precipitation in either of these conditions. At autopsy, uric acid precipitates are found in the lumen of the dilated proximal tubules. Treatment aimed at reducing the formation of uric acid, accelerating urination and increasing the proportion of the more soluble ionized form of uric acid (monosodium urate) leads to a reversal of the process.

Nephrolithiasis. In the United States, gout affects 10-25% of the population, while the number of people with uric acid stones is approximately 0.01%. The main factor contributing to the formation of uric acid stones is increased excretion of uric acid. Hyperuricaciduria may result from primary gout, an inborn error of metabolism leading to increased uric acid production, myeloproliferative disease, and other neoplastic processes. If uric acid excretion in urine exceeds 1100 mg/day, the incidence of stone formation reaches 50%. The formation of uric acid stones also correlates with increased serum urate concentration: at a level of 130 mg/l and above, the stone formation rate reaches approximately 50%. Other factors contributing to the formation of uric acid stones include: 1) excessive acidification of urine; 2) urine concentration; 3) (probably) a violation of the composition of urine, affecting the solubility of uric acid itself.

In patients with gout, calcium-containing stones are more often found; their frequency in gout reaches 1-3%, while in the general population it is only 0.1%. Although the mechanism of this association remains unclear, hyperuricemia and hyperuricaciduria are detected with a high frequency in patients with calcium stones. Uric acid crystals could serve as a nucleus for the formation of calcium stones.

Associated conditions. Patients with gout typically suffer from obesity, hypertriglyceridemia, and hypertension. Hypertriglyceridemia in primary gout is closely related to obesity or alcohol consumption, and not directly to hyperuricemia. The incidence of hypertension in individuals without gout correlates with age, sex, and obesity. When these factors are taken into account, it turns out that there is no direct connection between hyperuricemia and hypertension. The increased incidence of diabetes is also likely to be related to factors such as age and obesity rather than directly to hyperuricemia. Finally, the increased incidence of atherosclerosis has been attributed to concurrent obesity, hypertension, diabetes, and hypertriglyceridemia.

Independent analysis of the role of these variables indicates highest value obesity. Hyperuricemia in obese individuals appears to be associated with both increased production and decreased excretion of uric acid. Chronic alcohol consumption also leads to its overproduction and insufficient excretion.

Rheumatoid arthritis, systemic lupus erythematosus, and amyloidosis rarely coexist with gout. The reasons for this negative association are unknown.

Acute gout should be suspected in any person with sudden onset of monoarthritis, especially in the distal joints of the lower extremities. In all these cases, aspiration of synovial fluid is indicated. The definitive diagnosis of gout is made based on the detection of monosodium urate crystals in leukocytes from the synovial fluid of the affected joint using polarizing light microscopy (Fig. 309-3). The crystals have a typical needle shape and negative birefringence. They can be detected in the synovial fluid of more than 95% of patients with acute gouty arthritis. The inability to detect urate crystals in the synovial fluid with a careful search and compliance with the necessary conditions allows us to exclude the diagnosis. Intracellular crystals have diagnostic value, but do not exclude the possibility of the simultaneous existence of another type of arthropathy.

Gout may be accompanied by infection or pseudogout (deposition of calcium pyrophosphate dihydrate). To rule out infection, one should Gram stain the synovial fluid and try to culture the flora. Calcium pyrophosphate dihydrate crystals exhibit weakly positive birefringence and are more rectangular than monosodium urate crystals. With polarizing light microscopy, the crystals of these salts are easily distinguished. Puncture of the joint with suction of synovial fluid does not need to be repeated during subsequent attacks, unless a different diagnosis is suspected.

Aspiration of synovial fluid retains its diagnostic value during asymptomatic intercritical periods. In more than 2/3 of aspirates from the first metatarsal joints of the digital phalanges in patients with asymptomatic gout, extracellular urate crystals can be detected. They are detected in less than 5% of people with hyperuricemia without gout.

Synovial fluid analysis is important in other ways as well. The total number of leukocytes in it can be 1-70 109/l or more. Polymorphonuclear leukocytes predominate. As in other inflammatory fluids, clots of mucin are found in it. The concentrations of glucose and uric acid correspond to those in the serum.

In patients in whom synovial fluid cannot be obtained or intracellular crystals cannot be detected, the diagnosis of gout can presumably be reasonably made if: 1) hyperuricemia is detected; 2) classic clinical syndrome and 3) severe response to colchicine. In the absence of crystals or this highly informative triad, the diagnosis of gout becomes hypothetical. A sharp improvement in the condition in response to treatment with colchicine is a strong argument in favor of the diagnosis of gouty arthritis, but still not a pathognomonic sign.

Rice. 309-3. Crystals of monosodium urate monohydrate in joint aspirate.

Acute gouty arthritis should be differentiated from mono- and polyarthritis of other etiologies. Gout is a common initial manifestation, and many diseases are characterized by tenderness and swelling of the first toe. These include soft tissue infection, purulent arthritis, inflammation joint capsule on the outer side of the first finger, local trauma, rheumatoid arthritis, degenerative arthritis with acute inflammation, acute sarcoidosis, psoriatic arthritis, pseudogout, acute calcific tendonitis, palindromic rheumatism, Reiter's disease and sporotrichosis. Sometimes gout can be confused with cellulitis, gonorrhea, fibrosis of the plantar and calcaneal surfaces, hematoma and subacute bacterial endocarditis with embolization or suppuration. Gout, when other joints are involved, such as the knee, must be differentiated from acute rheumatic fever, serum sickness, hemarthrosis, and involvement of peripheral joints in ankylosing spondylitis or inflammation of the intestine.

Chronic gouty arthritis should be distinguished from rheumatoid arthritis, inflammatory osteoarthritis, psoriatic arthritis, enteropathic arthritis and peripheral arthritis accompanied by spondyloarthropathy. Chronic gout is supported by a history of spontaneous relief of monoarthritis, gouty deposits, typical changes on a radiograph, and hyperuricemia. Chronic gout may resemble other inflammatory arthropathies. Existing effective treatments justify the effort to confirm or rule out the diagnosis.

Pathophysiology of hyperuricemia. Classification. Hyperuricemia is a biochemical sign and serves as a necessary condition for the development of gout. The concentration of uric acid in body fluids is determined by the ratio of the rates of its production and elimination. It is formed by the oxidation of purine bases, which can be of both exogenous and endogenous origin. About 2/3 of uric acid is excreted in the urine (300-600 mg/day), and about 1/3 is excreted through the gastrointestinal tract, where it is ultimately destroyed by bacteria. Hyperuricemia may be due to increased speed production of uric acid, reduced excretion by the kidneys, or both.

Hyperuricemia and gout can be divided into metabolic and renal (Table 309-1). With metabolic hyperuricemia, the production of uric acid is increased, and with hyperuricemia of renal origin, its excretion by the kidneys is reduced. It is not always possible to clearly distinguish between the metabolic and renal types of hyperuricemia. With careful examination, both mechanisms for the development of hyperuricemia can be detected in a large number of patients with gout. In these cases, the condition is classified according to its predominant component: renal or metabolic. This classification applies primarily to those cases where gout or hyperuricemia are the main manifestations of the disease, that is, when gout is not secondary to another acquired disease and does not represent a subordinate symptom of a congenital defect that initially causes some other serious disease, not gout. Sometimes primary gout has a specific genetic basis. Secondary hyperuricemia or secondary gout are cases when they develop as symptoms of another disease or as a result of taking certain pharmacological agents.

Table 309-1. Classification of hyperuricemia and gout

Overproduction of uric acid. Overproduction of uric acid, by definition, means excretion of more than 600 mg/day after following a purine-restricted diet for 5 days. Such cases appear to account for less than 10% of all cases of the disease. The patient has accelerated de novo synthesis of purines or increased circulation of these compounds. In order to imagine the basic mechanisms of the corresponding disorders, one should analyze the pattern of purine metabolism (Fig. 309-4).

Purine nucleotides - adenylic, inosinic and guanic acids (AMP, IMP and GMP, respectively) - are the end products of purine biosynthesis. They can be synthesized in one of two ways: either directly from purine bases, i.e. GMP from guanine, IMP from hypoxanthine and AMP from adenine, or de novo, starting from non-purine precursors and passing through a series of steps until the formation of IMP, which serves as a common intermediate purine nucleotide. Inosinic acid can be converted to either AMP or HMP. Once purine nucleotides are formed, they are used to synthesize nucleic acids, adenosine triphosphate (ATP), cyclic AMP, cyclic GMP, and some cofactors.

Rice. 309-4. Scheme of purine metabolism.

1 - amidophosphoribosyltransferase, 2 - hypoxanthine guanine phosphoribosyltransferase, 3 - PRPP synthetase, 4 - adenine phosphoribosyltransferase, 5 - adenosine deaminase, 6 - purine nucleoside phosphorylase, 7 - 5"-nucleotidase, 8 - xanthine oxidase.

Various purine compounds are broken down into purine nucleotide monophosphates. Guanic acid is converted through guanosine, guanine and xanthine to uric acid, IMP breaks down through inosine, hypoxanthine and xanthine to the same uric acid, and AMP can be deaminated to IMP and further catabolized through inosine to uric acid or converted to inosine in an alternative way with the intermediate formation of adenosine .

Despite the fact that the regulation of purine metabolism is quite complex, the main determinant of the rate of uric acid synthesis in humans appears to be the intracellular concentration of 5-phosphoribosyl-1-pyrophosphate (PRPP). As a rule, when the level of PRPP in the cell increases, the synthesis of uric acid increases, and when its level decreases, it decreases. Despite some exceptions, in most cases this is the case.

Excess uric acid production in a small number of adult patients is a primary or secondary manifestation of an inborn error of metabolism. Hyperuricemia and gout may be the primary manifestation of partial deficiency of hypoxanthine guanine phosphoribosyltransferase (reaction 2 in Fig. 309-4) or increased activity of PRPP synthetase (reaction 3 in Fig. 309-4). In Lesch-Nyhan syndrome, almost complete deficiency of hypoxanthine guanine phosphoribosyltransferase causes secondary hyperuricemia. These serious congenital anomalies are discussed in more detail below.

For the mentioned inborn errors of metabolism (hypoxanthine guanine phosphoribosyltransferase deficiency and excessive activity of PRPP synthetase), less than 15% of all cases of primary hyperuricemia due to increased uric acid production are determined. The reason for the increase in its production in most patients remains unclear.

Secondary hyperuricemia, associated with increased production of uric acid, can be due to many causes. In some patients, increased excretion of uric acid is due, as in primary gout, to accelerated de novo purine biosynthesis. In patients with glucose-6-phosphatase deficiency (type I glycogen storage disease), uric acid production is constantly increased, as well as de novo biosynthesis of purines is accelerated (see Chapter 313). Overproduction of uric acid with this enzyme abnormality is due to a number of mechanisms. Accelerated de novo purine synthesis may in part result from accelerated PRPP synthesis. In addition, the accelerated breakdown of purine nucleotides contributes to increased excretion of uric acid. Both of these mechanisms are triggered by a deficiency of glucose as an energy source, and uric acid production can be reduced by continuous correction of the hypoglycemia typical of this disease.

In most patients with secondary hyperuricemia due to excess production of uric acid, the main disorder is obviously an acceleration of the turnover of nucleic acids. Increased bone marrow activity or shortened life cycle of cells of other tissues, accompanied by accelerated turnover of nucleic acids, are characteristic of many diseases, including myeloproliferative and lymphoproliferative diseases, multiple myeloma, secondary polycythemia, pernicious anemia, some hemoglobinopathies, thalassemia, others hemolytic anemia, infectious mononucleosis and a number of carcinomas. Accelerated turnover of nucleic acids, in turn, leads to hyperuricemia, hyperuricaciduria and a compensatory increase in the rate of de novo purine biosynthesis.

Reduced excretion. In a large number of patients with gout, this rate of uric acid excretion is achieved only when the plasma urate level is 10-20 mg/l above normal (Fig. 309-5). This pathology is most pronounced in patients with normal uric acid production and is absent in most cases of its overproduction.

Urate excretion depends on glomerular filtration, tubular reabsorption and secretion. Uric acid is apparently completely filtered in the glomerulus and reabsorbed in the proximal tubule (i.e., undergoes presecretory reabsorption). In the underlying segments of the proximal tubules it is secreted, and in the second site of reabsorption - in the distal part of the proximal tubule - it is once again subject to partial reabsorption (postsecretory reabsorption). Although some of it may be reabsorbed in both the ascending limb of the loop of Henle and the collecting duct, these two sites are considered less important from a quantitative point of view. Attempts to more accurately elucidate the localization and nature of these latter areas and to quantify their role in the transport of uric acid in a healthy or sick person, as a rule, were unsuccessful.

Theoretically, impaired renal excretion of uric acid in most patients with gout could be caused by: 1) a decrease in filtration rate; 2) increased reabsorption or 3) decreased secretion rate. There is no definitive evidence for the role of any of these mechanisms as a major defect; it is likely that all three factors are present in patients with gout.

Many cases of secondary hyperuricemia and gout can be considered a result of decreased renal excretion of uric acid. A decrease in glomerular filtration rate leads to a decrease in the filtration load of uric acid and, thereby, to hyperuricemia; This is why hyperuricemia develops in patients with kidney pathology. In some kidney diseases (polycystic disease and lead nephropathy), other factors, such as decreased secretion of uric acid, have been postulated to play a role. Gout rarely complicates hyperuricemia secondary to renal disease.

One of the most important causes of secondary hyperuricemia is treatment with diuretics. The decrease in circulating plasma volume they cause leads to increased tubular reabsorption of uric acid, as well as to a decrease in its filtration. In hyperuricemia associated with diuretic use, a decrease in uric acid secretion may also be important. A number of other drugs also cause hyperuricemia through unknown renal mechanisms; These drugs include acetylsalicylic acid (aspirin) in low doses, pyrazinamide, nicotinic acid, ethambutol and ethanol.

Rice. 309-5. Rates of uric acid excretion at different plasma urate levels in individuals without gout (black symbols) and in individuals with gout (open symbols).

Large symbols indicate average values, small symbols indicate individual data for several average values ​​(the degree of dispersion within groups). Studies were conducted under basal conditions, after RNA ingestion, and after lithium urate administration (by: Wyngaarden. Reproduced with permission from Academic Press).

It is believed that impaired renal excretion of uric acid is an important mechanism for hyperuricemia, which accompanies a number of pathological conditions. In hyperuricemia associated with adrenal insufficiency and nephrogenic diabetes insipidus, a decrease in circulating plasma volume may play a role. In a number of situations, hyperuricemia is considered to be the result of competitive inhibition of uric acid secretion by excess organic acids, which are secreted, apparently, using the same mechanisms of the renal tubules as uric acid. Examples include fasting (ketosis and free fatty acids), alcoholic ketosis, diabetic ketoacidosis, maple syrup disease, and lactic acidosis of any cause. In conditions such as hyperpara- and hypoparathyroidism, pseudohypoparathyroidism and hypothyroidism, hyperuricemia may also have a renal basis, but the mechanism of occurrence of this symptom is unclear.

Pathogenesis of acute gouty arthritis. The reasons that cause the initial crystallization of monosodium urate in the joint after a period of asymptomatic hyperuricemia for approximately 30 years are not fully understood. Persistent hyperuricemia eventually leads to the formation of microdeposits in the squamous cells of the synovium and, probably, to the accumulation of monosodium urate in cartilage on proteoglycans with a high affinity for it. For one reason or another, apparently including trauma with the destruction of microdeposits and acceleration of the turnover of cartilage proteoglycans, urate crystals are occasionally released into the synovial fluid. Other factors, such as low joint temperature or inadequate reabsorption of water and urate from synovial fluid, can also accelerate its deposition.

When a sufficient number of crystals are formed in the joint cavity, an acute attack is provoked by a number of factors, including: 1) phagocytosis of crystals by leukocytes with the rapid release of chemotaxis protein from these cells; 2) activation of the kallikrein system; 3) activation of complement with the subsequent formation of its chemotactic components: 4) the final stage of rupture of leukocyte lysosomes by urate crystals, which is accompanied by a violation of the integrity of these cells and the release of lysosomal products into the synovial fluid. While some progress has been made in understanding the pathogenesis of acute gouty arthritis, questions regarding the factors determining the spontaneous cessation of an acute attack and the effect of colchicine still await answers.

Treatment. Treatment for gout includes: 1) if possible, quick and careful relief of an acute attack; 2) prevention of relapse of acute gouty arthritis; 3) prevention or regression of complications of the disease caused by the deposition of monosubstituted sodium urate crystals in the joints, kidneys and other tissues; 4) prevention or regression accompanying symptoms such as obesity, hypertriglyceridemia or hypertension; 5) prevention of the formation of uric acid kidney stones.

Treatment for an acute attack of gout. For acute gouty arthritis, anti-inflammatory treatment is carried out. The most commonly used is colchicine. It is prescribed for oral administration, usually at a dose of 0.5 mg every hour or 1 mg every 2 hours, and treatment is continued until: 1) the patient’s condition improves; 2) there will be no adverse reactions from the gastrointestinal tract or 3) the total dose of the drug will not reach 6 mg due to the lack of effect. Colchicine is most effective if treatment is started soon after symptoms appear. In the first 12 hours of treatment, the condition improves significantly in more than 75% of patients. However, in 80% of patients, the drug causes adverse reactions from the gastrointestinal tract, which may appear before clinical improvement or simultaneously with it. When administered orally, maximum plasma levels of colchicine are achieved after approximately 2 hours. Therefore, it can be assumed that colchicine administered at 1.0 mg every 2 hours is less likely to cause a toxic dose to accumulate before manifestation. therapeutic effect. Since, however, therapeutic effect associated with leukocyte rather than plasma colchicine levels, the effectiveness of the treatment regimen requires further evaluation.

With intravenous administration of colchicine, side effects from the gastrointestinal tract do not occur, and the patient's condition improves faster. After a single administration, the level of the drug in leukocytes increases, remaining constant for 24 hours, and can be determined even after 10 days. As an initial dose, 2 mg should be administered intravenously, and then, if necessary, repeat the administration of 1 mg twice with an interval of 6 hours. When administering colchicine intravenously, special precautions should be taken. It has an irritating effect and, if it enters the tissue surrounding the vessel, can cause severe pain and necrosis. It is important to remember that the intravenous route of administration requires care and that the drug should be diluted in 5-10 volumes of normal saline solution, and continue the infusion for at least 5 minutes. Both oral and parenteral administration of colchicine can suppress bone marrow function and cause alopecia, liver cell failure, mental depression, seizures, ascending paralysis, respiratory depression and death. Toxic effects are more likely in patients with pathology of the liver, bone marrow or kidneys, as well as in those receiving maintenance doses of colchicine. In all cases, the dose of the drug must be reduced. It should not be prescribed to patients with neutropenia.

Other anti-inflammatory drugs are also effective for acute gouty arthritis, including indomethacin, phenylbutazone, naproxen, and fenoprofen.

Indomethacin can be prescribed for oral administration at a dose of 75 mg, after which the patient should receive 50 mg every 6 hours; treatment with these doses continues the next day after the symptoms disappear, then the dose is reduced to 50 mg every 8 hours (three times) and to 25 mg every 8 hours (also three times). Side effects of indomethacin include gastrointestinal disturbances, sodium retention, and central nervous system symptoms. nervous system. Although these doses may cause side effects in up to 60% of patients, indomethacin is generally better tolerated than colchicine and is probably the drug of choice for acute gouty arthritis. To increase the effectiveness of treatment and reduce the manifestations of pathology, the patient should be warned that taking anti-inflammatory drugs should be started at the first sensation of pain. Drugs that stimulate uric acid excretion and allopurinol are ineffective in an acute attack of gout.

At acute gout, especially when colchicine and nonsteroidal anti-inflammatory drugs are contraindicated or ineffective, systemic or local (i.e., intra-articular) administration of glucocorticoids is beneficial. For systemic administration, whether oral or intravenous, should be given in moderate doses over several days, as the concentration of glucocorticoids decreases rapidly and their effect ceases. Intra-articular administration of a long-acting steroid drug (for example, triamsinolone hexacetonide at a dose of 15-30 mg) can stop an attack of monoarthritis or bursitis within 24-36 hours. This treatment is especially appropriate if it is impossible to use a standard drug regimen.

Prevention. After stopping an acute attack, a number of measures are used to reduce the likelihood of relapse. These include: 1) daily prophylactic administration of colchicine or indomethacin; 2) controlled reduction of body weight in obese patients; 3) elimination of known precipitating factors, e.g. large quantities alcohol or foods rich in purines; 4) use of antihyperuricemic drugs.

Daily use of small doses of colchicine effectively prevents the development of subsequent acute attacks. Colchicine in a daily dose of 1-2 mg is effective in almost 1/4 of patients with gout and is ineffective in approximately 5% of patients. In addition, this treatment program is safe and has virtually no side effects. However, if the serum urate concentration is not maintained within normal limits, the patient will only be spared from acute arthritis, and not from other manifestations of gout. Maintenance treatment with colchicine is especially indicated during the first 2 years after starting antihyperuricemic drugs.

Prevention or stimulation of the reverse development of gouty deposits of monosubstituted sodium urate in tissues. Antihyperuricemic drugs are quite effective in reducing serum urate concentrations, so they should be used in patients with: 1) one or more attacks of acute gouty arthritis; 2) one gouty deposit or more; 3) uric acid nephrolithiasis. The purpose of their use is to maintain serum urate levels below 70 mg/l; i.e., at the minimum concentration at which urate saturates the extracellular fluid. This level can be achieved with drugs that increase renal excretion of uric acid or by decreasing the production of uric acid. Antihyperuricemic agents generally do not have anti-inflammatory effects. Uricosuric drugs reduce serum urate levels by increasing its renal excretion. Although a large number of substances have this property, the most effective ones used in the United States are probenecid and sulfinpyrazone. Probenecid is usually prescribed at an initial dose of 250 mg twice daily. Over several weeks, it is increased to ensure a significant reduction in serum urate concentration. In half of the patients this can be achieved with a total dose of 1 g/day; maximum dose should not exceed 3.0 g/day. Since the half-life of probenecid is 6-12 hours, it should be taken in equal doses 2-4 times a day. Major side effects include hypersensitivity, skin rash and gastrointestinal symptoms. Despite rare cases of toxicity, these adverse reactions force almost 1/3 of patients to stop treatment.

Sulfinpyrazone is a metabolite of phenylbutazone that lacks anti-inflammatory effects. Treatment with it begins at a dose of 50 mg twice a day, gradually increasing the dose to a maintenance level of 300-400 mg/day 3-4 times. Maximum efficiency daily dose is 800 mg. Side effects are similar to those of probenecid, although the incidence of bone marrow toxicity may be higher. Approximately 25% of patients stop taking the drug for one reason or another.

Probenecid and sulfinpyrazone are effective in most cases of hyperuricemia and gout. In addition to drug intolerance, treatment failure may be due to a violation of the drug regimen, concomitant use of salicylates, or impaired renal function. Acetylsalicylic acid (aspirin) at any dose blocks the uricosuric effect of probenecid and sulfinpyrazone. They become less effective when creatinine clearance is below 80 ml/min and cease action at creatinine clearance of 30 ml/min.

With a negative urate balance caused by treatment with uricosuric drugs, the serum urate concentration decreases and urinary excretion of uric acid exceeds the baseline level. Continuation of treatment causes the mobilization and release of excess urate, its amount in the serum decreases, and the excretion of uric acid in the urine almost reaches its original values. A transient increase in its excretion, usually lasting only a few days, can cause the formation of kidney stones in 1/10 of the patients. In order to avoid this complication, uricosuric drugs should be started with small doses, gradually increasing them. Maintain increased urine output with adequate hydration and alkalinization of urine by oral administration sodium bicarbonate alone or together with acetazolamide reduces the likelihood of stone formation. The ideal candidate for treatment with uricosuric drugs is a patient under the age of 60 years, following a normal diet, with normal function kidneys and uric acid excretion less than 700 mg/day, who has no history of kidney stones.

Hyperuricemia can also be corrected with allopurinol, which reduces the synthesis of uric acid. It inhibits xanthine oxidase (see reaction 8 in Fig. 309-4), which catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Although allopurinol has a half-life of only 2-3 hours in the body, it is converted primarily to oxypurinol, which is an equally effective xanthine oxidase inhibitor but with a half-life of 18-30 hours. In most patients, a dose of 300 mg/day is effective. Because of the long half-life of allopurinol's main metabolite, it can be administered once daily. Because oxypurinol is excreted primarily in the urine, its half-life is prolonged in renal failure. In this regard, in case of severe renal impairment, the dose of allopurinol should be halved.

Serious side effects of allopurinol include gastrointestinal dysfunction, skin rashes, fever, toxic epidermal necrolysis, alopecia, bone marrow suppression, hepatitis, jaundice and vasculitis. The overall incidence of side effects reaches 20%; they often develop in renal failure. Only in 5% of patients their severity forces them to stop treatment with allopurinol. When prescribing it, drug-drug interactions should be taken into account, as it increases the half-life of mercaptopurine and azathioprine and increases the toxicity of cyclophosphamide.

Allopurinol is preferred to uricosuric drugs for: 1) increased (more than 700 mg/day when following a general diet) excretion of uric acid in the urine; 2) impaired renal function with creatinine clearance less than 80 ml/min; 3) gouty deposits in the joints, regardless of kidney function; 4) uric acid nephrolithiasis; 6) gout that is not affected by uricosuric drugs due to their ineffectiveness or intolerance. In rare cases of ineffectiveness of each drug used separately, allopurinol can be used simultaneously with any uricosuric agent. This does not require a change in drug dose and is usually accompanied by a decrease in serum urate levels.

No matter how rapid and pronounced the decrease in serum urate levels is, acute gouty arthritis may develop during treatment. In other words, starting treatment with any antihyperuricemic drug may precipitate an acute attack. In addition, with large gouty deposits, even against the background of a decrease in the severity of hyperuricemia for a year or more, relapses of attacks may occur. Therefore, before starting antihyperuricemic drugs, it is advisable to start prophylactic colchicine and continue it until the serum urate level is within the normal range for at least a year or until all gouty deposits have dissolved. Patients should be aware of the possibility of exacerbations in the early period of treatment. Most patients with large deposits in the joints and/or renal failure should sharply limit their dietary intake of purines.

Prevention of acute uric acid nephropathy and treatment of patients. In acute uric acid nephropathy, intensive treatment must be started immediately. Initially, urine output should be increased with large fluid loads and diuretics, such as furosemide. The urine is alkalinized so that uric acid is converted into the more soluble monosodium urate. Alkalinization is achieved using sodium bicarbonate - alone or in combination with acetazolamide. Allopurinol should also be administered to reduce the formation of uric acid. Its initial dose in these cases is 8 mg/kg per day once. After 3-4 days, if renal failure persists, the dose is reduced to 100-200 mg/day. For uric acid kidney stones, treatment is the same as for uric acid nephropathy. In most cases, it is sufficient to combine allopurinol with large amounts of fluid intake only.

Management of patients with hyperuricemia. Examination of patients with hyperuricemia is aimed at: 1) identifying its cause, which may indicate another serious disease; 2) assessment of damage to tissues and organs and its degree; 3) identification of associated disorders. In practice, all these problems are solved simultaneously, since the decision regarding the meaning of hyperuricemia and treatment depends on the answer to all these questions.

The most important results for hyperuricemia are urine test results for uric acid. If there is a history of urolithiasis, a survey of the abdominal cavity and intravenous pyelography are indicated. If kidney stones are detected, they may be useful analysis for uric acid and other components. In case of joint pathology, it is advisable to examine the synovial fluid and take x-rays of the joints. If there is a history of lead exposure, urinary excretion following a calcium-EDTA infusion may be necessary to diagnose gout associated with lead poisoning. If increased uric acid production is suspected, determination of the activity of hypoxanthine guanine phosphoribosyltransferase and PRPP synthetase in erythrocytes may be indicated.

Management of patients with asymptomatic hyperuricemia. The question of the need to treat patients with asymptomatic hyperuricemia does not have a clear answer. As a rule, treatment is not required unless: 1) the patient has no complaints; 2) there is no family history of gout, nephrolithiasis, or renal failure, or 3) uric acid excretion is not too high (more than 1100 mg/day).

Other disorders of purine metabolism, accompanied by hyperuricemia and gout. Hypoxanthine guanine phosphoribosyltransferase deficiency. Hypoxanthine guanine phosphoribosyltransferase catalyzes the conversion of hypoxanthine to inosinic acid and guanine to guanosine (see reaction 2 in Fig. 309-4). PRPP serves as a phosphoribosyl donor. Hypoxanthine guanyl phosphoribosyltransferase deficiency leads to a decrease in the consumption of PRPP, which accumulates in higher than normal concentrations. Excess PRPP accelerates de novo purine biosynthesis and consequently increases uric acid production.

Lesch-Nyhan syndrome is an X-linked disorder. A characteristic biochemical disorder with it is a pronounced deficiency of hypoxanthine guanine phosphoribosyltransferase (see reaction 2 in Fig. 309-4). Patients experience hyperuricemia and excessive overproduction of uric acid. In addition, they develop peculiar neurological disorders, characterized by self-mutilation, choreoathetosis, spastic muscle condition, as well as delayed growth and mental development. The incidence of this disease is estimated at 1:100,000 newborns.

Approximately 0.5-1.0% of adult patients with gout with excess production of uric acid have a partial deficiency of hypoxanthine guanine phosphoribosyltransferase. Usually their gouty arthritis manifests itself in at a young age(15-30 years), the frequency of uric acid nephrolithiasis is high (75%), sometimes some neurological symptoms are associated, including dysarthria, hyperreflexia, impaired coordination and/or mental retardation. The disease is inherited as an X-linked trait, so it is transmitted to men from female carriers.

The enzyme whose deficiency causes this disease (hypoxanthine guanine phosphoribosyltransferase) is of significant interest to geneticists. With the possible exception of the globin gene family, the hypoxanthine guanine phosphoribosyltransferase locus is the most studied single gene in humans.

Human hypoxanthine guanine phosphoribosyltransferase was purified to a homogeneous state, and its amino acid sequence was determined. Normally, its relative molecular weight is 2470, and the subunit consists of 217 amino acid residues. The enzyme is a tetramer consisting of four identical subunits. There are also four variant forms of hypoxanthine guanine phosphoribosyltransferase (Table 309-2). In each of them, the replacement of one amino acid leads to either a loss of the catalytic properties of the protein or a decrease in the constant concentration of the enzyme due to a decrease in synthesis or acceleration of the breakdown of the mutant protein.

The DNA sequence complementary to the messenger RNA (mRNA) that encodes gyloxanthine guanine phosphoribosyltransferase has been cloned and deciphered. As a molecular probe, this sequence was used to identify carrier status in women at risk in whom carrier status could not be detected by conventional means. The human gene was transferred into a mouse using a bone marrow transplant infected with a vectored retrovirus. The expression of human hypoxanthine guanine phosphoribosyltransferase in the mouse treated in this way has been determined with certainty. Recently, a transgenic line of mice has also been obtained in which the human enzyme is expressed in the same tissues as in humans.

The accompanying biochemical abnormalities that cause the pronounced neurological manifestations of Lesch-Nyhan syndrome have not been sufficiently deciphered. Post-mortem examination of the patients' brains revealed signs of a specific defect in the central dopaminergic pathways, especially in the basal ganglia and nucleus accumbens. Relevant in vivo data were obtained using positron emission tomography (PET) in patients with hypoxanthine guanine phosphoribosyltransferase deficiency. In the majority of patients examined by this method, a disorder of 2-fluoro-deoxyglucose metabolism in the caudate nucleus was detected. The relationship between the pathology of the dopaminergic nervous system and the disorder of purine metabolism remains unclear.

Hyperuricemia caused by partial or complete deficiency of hypoxanthine guanine phosphoribosyltransferase can be successfully treated with the xanthine oxidase inhibitor allopurinol. In this case, a small number of patients develop xanthine stones, but most of them with kidney stones and gout are cured. There are no specific treatments for neurological disorders associated with Lesch-Nyhan syndrome.

Variants of PRPP synthetase. Several families have been identified whose members had increased activity of the enzyme PRPP synthetase (see reaction 3 in Fig. 309-4). All three known types of mutant enzymes have increased activity, which leads to an increase in the intracellular concentration of PRPP, acceleration of purine biosynthesis and increased excretion of uric acid. This disease is also inherited as an X-linked trait. As with partial deficiency of hypoxanthine guanine phosphoribosyltransferase, with this pathology, gout usually develops in the second or third 10 years of life and uric acid stones often form. In several children, increased activity of PRPP synthetase was combined with nerve deafness.

Other disorders of purine metabolism. Adenine phosphoribosyltransferase deficiency. Adenine phosphoribosyltransferase catalyzes the conversion of adenine to AMP (see reaction 4 in Fig. 309-4). The first person who was found to be deficient in this enzyme was heterozygous for this defect and had no clinical symptoms. It was then found that heterozygosity for this trait is quite widespread, probably with a frequency of 1:100. Currently, 11 homozygotes for deficiency of this enzyme have been identified, whose kidney stones consisted of 2,8-dioxyadenine. Because of its chemical similarity, 2,8-dihydroxyadenine is easily confused with uric acid, so these patients were initially misdiagnosed as uric acid nephrolithiasis.

Table 309-2. Structural and functional disorders in mutant forms of human hypoxanthine guanine phosphoribosyltransferase

Note. PRPP means 5-phosphoribosyl-1-pyrophosphate, Arg means arginine, Gly means glycine, Ser means serine. Leu - leucine, Asn - asparagine. Asp- aspartic acid, ? - replaced (according to Wilson et al.).

For adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency, see Chap. 256.

Xanthine oxidase deficiency. Xanthine oxidase catalyzes the oxidation of hypoxanthine to xanthine, xanthine to uric acid, and adenine to 2,8-dioxyadenine (see reaction 8 in Fig. 309-4). Xanthinuria, the first congenital disorder of purine metabolism deciphered at the enzymatic level, is caused by a deficiency of xanthine oxidase. As a result, in patients with xanthinuria, hypouricemia and hypouricaciduria are detected, as well as increased urinary excretion of oxypurines-hypoxanthine and xanthine. Half of the patients do not complain, and in 1/3 xanthine stones form in the urinary tract. Several patients developed myopathy, and three developed polyarthritis, which could be a manifestation of crystal-induced synovitis. In the development of each of the symptoms, great importance is attached to the precipitation of xanthine.

In four patients, congenital xanthine oxidase deficiency was combined with congenital sulfate oxidase deficiency. The clinical picture in newborns was dominated by severe neurological pathology, which is characteristic of isolated sulfate oxidase deficiency. Despite the fact that the main defect was postulated to be a deficiency of the molybdate cofactor necessary for the functioning of both enzymes, treatment with ammonium molybdate was ineffective. A patient who was completely on parenteral nutrition developed a disease simulating combined deficiency of xanthine oxidase and sulfate oxidase. After treatment with ammonium molybdate, enzyme function was completely normalized, which led to clinical recovery.

Myoadenylate deaminase deficiency. Myoadenylate deaminase, an isoenzyme of adenylate deaminase, is found only in skeletal muscle. The enzyme catalyzes the conversion of adenylate (AMP) to inosinic acid (IPA). This reaction is component purine nucleotide cycle and appears to be important for maintaining the processes of energy production and utilization in skeletal muscle.

Deficiency of this enzyme is detected only in skeletal muscle. In most patients with physical activity myalgia, muscle spasms and a feeling of fatigue appear. Approximately 1/3 of patients complain of muscle weakness even in the absence of exercise. Some patients have no complaints.

The disease usually manifests itself in childhood and adolescence. Clinical symptoms with it are the same as with metabolic myopathy. Creatinine kinase levels are elevated in less than half of the cases. Electromyographic studies and conventional histology of muscle biopsies can detect nonspecific changes. Presumably, adenylate deaminase deficiency can be diagnosed based on the results of a performance test of the ischemic forearm. In patients with deficiency of this enzyme, ammonia production is reduced because the deamination of AMP is blocked. The diagnosis should be confirmed by direct determination of AMP deaminase activity in a skeletal muscle biopsy, since. reduced ammonia production during work is also characteristic of other myopathies. The disease progresses slowly and in most cases leads to some decrease in performance. There is no effective specific therapy.

Along with other diseases, disorders of purine metabolism are also important disease, the treatment of which must be given special importance. First of all, it is a violation of the metabolism of useful substances in the body and the metabolism of proteins, which in turn can be expressed in several diseases, such as: renal failure, nephropathy, gout. In most cases, a disorder of purine metabolism is a childhood disease, but very often it can occur in adults.

Symptoms of the disease.

The symptoms of the disease are very similar to those with metabolic disorders (metabolism of nutrients in the body and their absorption) - metabolic myopathy. The disease is characterized by elevated levels of creatinine kinase (in most cases). Other, nonspecific symptoms of the disease can be determined using an electromyographic study.
In patients who have a disorder of purine metabolism, ammonia production is very low, and performance and appetite also decrease. Patients feel lethargic, sometimes developing very great weakness in the body. Children who suffer from metabolic disorders for a long time often remain mentally undeveloped and have a tendency to develop autism. In rare cases, children (and sometimes adults) experience seizures, convulsions, and the psychomotor development of the individual is greatly inhibited.
Diagnostics cannot give a 100% result in determining the correctness of the disease, since it has many similar indicators with other disorders in the homeostasis of the body, but in general terms and with long-term observation of the patient’s tests, a disorder of purine metabolism can be determined. The diagnosis is based, first of all, on the complete absence of enzyme activity in the kidneys, liver and skeletal muscles. Using a number of tests, partial deficiency can be determined in fibroblasts and lymphocytes. Specific treatment that would be focused on achieving results in the treatment of dysfunction of these enzymes has not yet been developed and can only rely on the generally accepted comprehensive methodology.

Purine base exchange

The optimal level of protein synthesis and the creation of new ones is the basis for the correct, systematic exchange of purine bases, since they are the most important component of the proper functioning of the body and contribute to the release of a sufficient number of enzymes. Correct exchange purine bases will ensure stability in metabolism and the balance of energy that is released during the exchange of useful substances.
You should carefully monitor the metabolism in the body, as this will affect not only excess weight (as many people who have heard about the causes of excess weight believe), but also directly on the proper development of all body tissues. A deficiency or slowdown in the metabolism of important substances will slow down tissue development. The synthesis of puric acids is the main catalyst for all division processes in human tissues, since these are protein formations that are supervised by the beneficial components that are delivered to the tissue thanks to these processes. Another symptom that can be detected when diagnosing metabolic disorders is an increased ratio of metabolic products in uric acid, in which they accumulate during the breakdown of purine nucleotides.
Disorders of purine metabolism, symptoms and treatment of purine metabolism in the body, diagnostics of software are actions that should be carried out systematically, especially in children and young men, in whom the disease manifests itself most often.
Where do these purine bases come from?
Purine bases enter the body directly with food, or can be synthesized in the cells themselves. The process of synthesis of purine bases is a rather complex, multi-stage process that largely takes place in the liver tissue. The synthesis of purine bases can be carried out in a variety of ways, in which adenine in the nucleotides and ordinary, free adenine are broken down, converted into other components, which are further converted into xathin and, as a consequence, further converted into uric acid. In primates and humans, this particular product is the final product of the process of synthesis of purine bases and, being unnecessary for the body, is excreted from it in the urine.
Violation of purine bases and their synthesis leads to the formation of uric acid more than the prescribed norm and its accumulation in the form of urates. As a result, uric acid is poorly absorbed and enters the blood, exceeding the permissible, accepted norm of 360-415 µmol/l. This state of the body, as well as the amount of substances allowed, may vary depending on the person’s age, overall weight, gender, proper kidney function and alcohol consumption.
As this disease progresses, hyperuricemia may occur—an increased amount of urate in the blood plasma. If this disease is not treated, then soon there is a possibility of gout. This is a type of disorder of purine metabolism in the body, which is accompanied by a disorder of fat metabolism. As a consequence of this - excess weight, atherosclerosis and the possible development of coronary heart disease, high blood pressure.

Treatment of the disease.

Metabolic disorders (the treatment of which is described below) implies complex treatment, which is based primarily on strict diets containing foods with a reduced amount of purine bases (meat, vegetables), but medicinal methods of treatment can also be used:

• Balancing and stabilizing purine metabolism through fortification.
• Establishment of metabolic acidosis and regulation of the acidic environment of urine.
• Monitoring and stabilization of the patient’s blood pressure throughout the day.
• Establishment and maintenance of hyperlipidemia norms.
• Complex treatment of possible complications of purine metabolism in the body (treatment of pyelonephritis)

Treatment of PO in the body can be carried out either in a hospital or independently after consultation with a doctor.

Violations and their causes in alphabetical order:

disorder of purine metabolism -

Purine metabolism is a set of processes of synthesis and breakdown of purine nucleotides. Purine nucleotides consist of a nitrogenous purine base residue, a ribose carbohydrate (deoxyribose) linked by a b-glycosidic bond to the nitrogen atom of the purine base, and one or more phosphoric acid residues attached by an ester bond to the carbon atom of the carbohydrate component.

What diseases cause purine metabolism disorders:

To the most important violations purine metabolism include excessive formation and accumulation of uric acid, for example in gout and Lesch-Nyhan syndrome.

The latter is based on a hereditary deficiency of the enzyme hypoxanthine phosphatidyltransferase, as a result of which free purines are not reused, but are oxidized into uric acid.

In children with Lesha-Nyhan syndrome, inflammatory and dystrophic changes are observed. caused by the deposition of uric acid crystals in tissues: the disease is characterized by delayed mental and physical development.

Disturbances in purine metabolism are accompanied by disturbances in fat (lipid) metabolism. Therefore, in many patients, body weight increases, atherosclerosis of the aorta and coronary arteries progresses, coronary heart disease develops, and blood pressure persistently increases.

Gout is often accompanied by diabetes mellitus, cholelithiasis, and significant changes occur in the kidneys.

Attacks of gout are provoked by alcohol intake, hypothermia, physical and mental stress, and usually begin at night with severe pain.

Which doctors should you contact if a purine metabolism disorder occurs:

Have you noticed a disorder in purine metabolism? Do you want to know more detailed information or do you need an inspection? You can make an appointment with a doctor– clinic Eurolab always at your service! The best doctors will examine you and study you external signs and will help you identify the disease by symptoms, advise you and provide the necessary assistance. you also can call a doctor at home. Clinic Eurolab open for you around the clock.

How to contact the clinic:
Phone number of our clinic in Kyiv: (+38 044) 206-20-00 (multi-channel). The clinic secretary will select a convenient day and time for you to visit the doctor. Our coordinates and directions are indicated. Look in more detail about all the clinic’s services on it.

(+38 044) 206-20-00

If you have previously performed any research, Be sure to take their results to a doctor for consultation. If the studies have not been performed, we will do everything necessary in our clinic or with our colleagues in other clinics.

Is your purine metabolism disrupted? It is necessary to take a very careful approach to your overall health. People don't pay enough attention symptoms of diseases and do not realize that these diseases can be life-threatening. There are many diseases that at first do not manifest themselves in our body, but in the end it turns out that, unfortunately, it is too late to treat them. Each disease has its own specific signs, characteristic external manifestations - the so-called symptoms of the disease. Identifying symptoms is the first step in diagnosing diseases in general. To do this, you just need to do it several times a year. be examined by a doctor, in order not only to prevent a terrible disease, but also to maintain a healthy spirit in the body and the organism as a whole.

If you want to ask a doctor a question, use the online consultation section, perhaps you will find answers to your questions there and read self care tips. If you are interested in reviews about clinics and doctors, try to find the information you need on. Also register on medical portal Eurolab to keep abreast of the latest news and information updates on the site, which will be automatically sent to you by email.

The symptom chart is for educational purposes only. Do not self-medicate; For all questions regarding the definition of the disease and methods of its treatment, consult your doctor. EUROLAB is not responsible for the consequences caused by the use of information posted on the portal.

If you are interested in any other symptoms of diseases and types of disorders, or you have any other questions or suggestions, write to us, we will definitely try to help you.