How to restore purine metabolism. Gout: purine metabolism disorder, gouty arthritis

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 monohydrate monohydrate sodium urate can be detected in leukocytes from the synovial fluid; 3) large deposits monosodium urate monohydrate (tophi), mainly in and around the joints of the extremities, sometimes leading to severe lameness and joint deformities; 4) damage to the kidneys, including interstitial tissues and blood vessels; 5} 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 levels greater 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, and blood pressure are also correlated with serum urate concentration. 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 common clinical manifestation of a 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 from the ka group it usually does not appear until menopause. In contrast, with some enzyme defects (hereinafter), 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. 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 stage 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 occurs before the first stage 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 ptups varies, but is still limited, they are interspersed with asymptomatic periods. In at least half of the cases, the first ptup begins in the joint of the metatarsal bone of the first toe. Ultimately, 90% of patients experience 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 ptupy. After the first toe, the process involves the joints of the metatarsal bones, ankles, heels, knees, wrist bones, fingers and elbows. Acute pain attacks in the shoulder and hip joints, joints of the spine, sacroiliac, sternoclavicular and lower jaw 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. Ptup can be triggered by a number of specific reasons, such as injury, consumption of alcohol and certain medications, dietary errors, 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 even the feeling of a cold shower is combined. 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 stage 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 stage 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 ptups, each of which becomes increasingly longer, and remissions become less and less complete. With subsequent ptups, several joints are usually involved in the process; the ptups 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 episode.

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 accumulations of monosodium urate crystals appear in cartilage, synovial membranes, tendons and soft tissues. The rate of formation of these accumulations depends on the degree and duration of hyperuricemia and the severity of kidney damage. The classic, but certainly not the most common site of accumulation is the helix or antihelix of the auricle (309-1). Gouty deposits are also often localized along the ulnar surface of the forearm in the form of protrusions of the elbow bursa (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 fluid 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 monosubstituted sodium urate in the aspirate of kthalls (using a polarizing microscope) allows us to classify the nodule as gouty. Gout deposits rarely become infected. In patients with noticeable gouty nodules, acute arthritis appears to occur less frequently and is less severe than in patients without these deposits. Chronic gouty nodules rarely form before the onset of arthritis.

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

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 the result of the deposition of monosodium urate kthalls in the interstitial tissue of the kidneys, and secondly, obstructive uropathy, caused by the formation of uric acid kthalls 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 the clinical significance of these deposits is 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 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 may therefore enhance talc 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 that contribute to the formation of uric acid stones include: 1) excessive acidification of urine; 2) concentrated urine; 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 relationship 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 points to obesity as having the greatest importance. 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 based on the detection of monosodium urate crystals in leukocytes from the synovial fluid of the affected joint using polarizing light microscopy (309-3). Crystals have a typical needle-like 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 synovial fluid with a thorough search and compliance with the necessary conditions allows us to exclude the diagnosis. Intracellular talli 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 polarization 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 at subsequent procedures, 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 10 9 / 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 talli cannot be detected, the diagnosis of gout can presumably be reasonably made if: 1) hyperuricemia; 2) the classic clinical syndrome and 3) a pronounced reaction to colchicine are identified. In the absence of kthalls 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.

309-3. Crystals of sodium 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 of the 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 tendinitis, 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. Approximately 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 an increased rate of uric acid production, decreased renal excretion, 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 (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.

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 of 309-4) or increased activity of PRPP synthetase (reaction 3 of 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 denovo purine biosynthesis. In patients with glucose-6-phosphatase deficiency (type I glycogen storage disease), the production of uric acid is constantly increased, as well as de novo biosynthesis of purines is accelerated (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, other hemolytic anemias, infectious mononucleosis and a number carcinoma. 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 gout patients, this rate of uric acid excretion is achieved only when the plasma urate level is 10-20 mg/l above normal (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) a decrease in the rate of secretion. 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.

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 AcademicPress).

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 kthalls are formed in the joint cavity, acute arthritis is provoked by a number of factors, including: 1) phagocytosis of kthalls 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 cleavage of lysosomes of leukocytes by urate ctalls, 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 acute gouty arthritis and the effect of colchicine still await answers.

Treatment. Treatment for gout involves: 1) whenever possible, rapid and careful relief of acute arthritis; 2) prevention of relapse of acute gouty arthritis; 3) prevention or regression of complications of the disease caused by the deposition of monosodium urate crystals in the joints, kidneys and other tissues; 4) prevention or regression of associated symptoms such as obesity, hypertriglyceridemia or hypertension; 5) prevention of the formation of uric acid kidney stones.

Treatment for acute 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) relief of the patient’s condition occurs; 2) adverse reactions from the gastrointestinal tract appear or 3) the total dose of the drug does 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, the maximum plasma level of colchicine is reached after approximately 2 hours. Therefore, it can be assumed that its administration at 1.0 mg every 2 hours is less likely to cause the accumulation of a toxic dose before the therapeutic effect occurs. Since, however, the therapeutic effect is related to the level of colchicine in leukocytes and not in plasma, 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 the infusion should be continued 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. 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 acute gout.

In acute gout, especially when colchicine and non-steroidal 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, moderate doses should be given over several days as glucocorticoid concentrations decrease 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 relieve monoarthritis or bursitis within 24-36 hours. This treatment is especially appropriate if it is impossible to use a standard drug regimen.

Prevention. After relief of an acute ptup, a number of measures are used to reduce the likelihood of relapse. These include: 1) daily prophylactic administration of colchicine or indomethacin; 2) controlled weight loss in obese patients; 3) elimination of known triggers, such as large amounts of alcohol or foods rich in purines; 4) use of antihyperuricemic drugs.

Daily intake 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 episodes of acute gouty arthritis; 2) one or more gouty deposits; 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; the 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. The maximum effective 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. Maintaining increased urinary output with adequate hydration and alkalinization of the urine by oral administration of sodium bicarbonate alone or with acetazolamide reduces the likelihood of stone formation. The ideal candidate for treatment with uricosurics is a patient under 60 years of age, on a regular diet, with normal renal function and uric acid excretion of less than 700 mg/day, and with no history of renal stones.

Hyperuricemia can also be corrected with allopurinol, which reduces the synthesis of uric acid. It inhibits xanthine oxidase (reaction 8 to 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, which is not amenable to the effects of 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 can provoke an acute pt. 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 ptup can 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) determining its cause, which may indicate another serious disease; 2) assessing 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, testing for uric acid and other components may be helpful. 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. Typically, no treatment is 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 (reaction 2 to 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 denovo purine biosynthesis and, therefore, 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 (reaction 2 to 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. Typically, their gouty arthritis manifests itself at a young age (15-30 years), the frequency of uric acid nephrolithiasis is high (75%), sometimes some neurological symptoms are combined, 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 from group ka, in whom carrier status could not be detected by conventional methods. 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.

Concomitant biochemical abnormalities that cause 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 disturbance in the metabolism of 2-fluoro-deoxyglucose in the caudate nucleus was detected. The relationship between the pathology of the dopaminergic nervous system and disorders 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 were identified whose members had increased activity of the enzyme PRPP synthetase (reaction 3 to 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 (reaction 4 to 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 stands for 5-phosphoribosyl-1-pyrophosphate, Arg for arginine, Gly for glycine, Ser for serine. Leu - leucine, Asn - asparagine. Asp-aspartic acid,®-replaced (according to Wilson et al.).

Adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency in Chapter 256.

Xanthine oxidase deficiency. Xanthine oxidase catalyzes the oxidation of hypoxanthine to xanthine, xanthine to uric acid and adenine to 2,8-dioxyadenine (reaction 8 to 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 ctallium-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 an integral part of the 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. Most patients experience myalgia, muscle spasms and a feeling of fatigue during physical activity. 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. Its clinical symptoms are the same as for 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.

Adenylsuccinase deficiency. Patients with adenylsuccinase deficiency are retarded in mental development and often suffer from autism. In addition, they suffer from convulsive seizures, their psychomotor development is delayed, and a number of movement disorders are noted. Urinary excretion of succinylaminoimidazole carboxamide riboside and succinyladenosine is increased. The diagnosis is made by detecting partial or complete absence of enzyme activity in the liver, kidneys or skeletal muscles. In lymphocytes and fibroblasts its partial deficiency is determined. The prognosis is unknown, and no specific treatment has been developed.