What Is the Connection Between Gout and Hyperuricemia?

Many well-known Western emperors suffered from gout in western history, so they called gout a monarch disease, so it has always been regarded as a wealthy disease with a close relationship with "meat and meat". The history of gout can be traced back to the 17th century. The famous neurologist Thomas Sydenham first described the symptoms of gout in detail, but the close relationship between gout and uric acid was not known until the 19th century. After 1950, one can accurately measure the blood uric acid value and use a polarized light microscope to observe the monosodium urate (MSU) crystals engulfed by polymorphonuclear leukocytes to confirm the diagnosis. Lesch-Nyhan syndrome discovered in the 1960s revealed the relationship between gout and purine metabolizing enzymes, hypoxanthine-guanine phosphoribosyl transferase (HGPRT). In recent years, molecular biology techniques have been used to discover that gout is associated with gene mutation or gene loss. In the 1980s, clinicians discovered a new phenomenon and called it a marker for cell energy crisis. It is common in some particularly ill patients in the ward, and they exercise vigorously. After normal people, long-term heavy drinkers, patients with glycogen storage disease type (von Gierke disease) and so on. Studies have found that these patients have a common pathogenic mechanism of hyperuricemia: the net degradation of ATP.

Gout and hyperuricemia

Gout is a disease caused by disorders of purine metabolism due to hereditary or acquired causes. Its clinical features are: hyperuricemia and the recurrence of gouty acute arthritis, goutstone deposition, goutstone chronic arthritis and joint deformities, often involving the kidneys and causing chronic interstitial nephritis and uric acidic kidney stones Formation can also cause acute renal failure caused by uric acid stones.

Overview of Gout and Hyperuricemia Diseases

Modern gout research was first described by Thomas Sydenham in 1683. He gave a detailed introduction to the clinical symptoms of gout with his 34 years of experience with gout. In 1776, Scheele clarified that kidney stones in gout patients were caused by uric acid. After several years, Woolaston isolated uric acid from the gout stones, and attributed the clinical pathology to uric acid. In 1856, Garrod proposed a special laboratory test for the diagnosis of gout by uric acid determination. Later, Fisher clarified the chemical structure of uric acid to determine that uric acid is the final product of purine metabolism. In recent years, molecular biology techniques have been used to discover that gout is associated with gene mutations or gene loss. In the 1980s, some scholars discovered that the common pathogenesis of hyperuricemia in gout patients is the net dagradetion, which is common in some wards. Particularly critical patients, such as acute myocardial infarction, normal people after intense exercise, status epilepticus, long-term heavy drinkers, patients with liver glycogenosis type 1 (von Gierke disease). The reason is that too much ATP is decomposed to increase its decomposition product, AMP. AMP can increase uric acid production by dephosphorylation to form adenosine and deamination to form hypoxanthine nucleotides.

After the Second World War, the number of cases of gout and hyperuricemia in the East has increased significantly. In recent years, epidemiological investigations have found that the incidence of gout in the East is even higher than that in the West. Today, people with gout in Taiwan and China are everywhere. Confined to a few elite officials and become a new civilization disease. A 1988 community study in Puli, Taiwan, China showed that the proportion of high uric acid in adults over 30 years of age is quite high. The prevalence rate reached 17.3%, of which 20.3% were male and 14% higher than female. In addition, according to the results of a large-scale community epidemiological survey in Jinhu Town, Jinmen County from 1991 to 1992, the prevalence of hyperuricemia in men was 25.8%, and the prevalence of hyperuricemia in women was 15.0%. Among them, the proportion of gout patients with hyperuricemia was 11.5% in men and 3% in women.

Gout is a group of diseases caused by disorders of purine metabolism and / or decreased uric acid excretion. Clinical features are hyperuricemia, recurrent acute monoarthritis, recurrent acute monoarthritis, sodium urate formation of tophus (tophus) deposits, and goutstone chronic arthritis. If not treated properly, eventually Less than 1% of patients with primary gout who develop gouty nephropathy are caused by a defect in purine metabolism enzymes and most of them are unknown. Clinically, gouty arthritis is the main manifestation and is often accompanied by hyperlipidemia and hypertension. Disease, diabetes, arteriosclerosis and coronary heart disease. Secondary gout can be caused by kidney disease, blood disease, and drugs. Gout is a complication.

The incidence of gout varies significantly from 0.13% to 0.37% in Europe and the United States to 10% of Maori adult males in New Zealand. With the development of society and living standards, the incidence has gradually increased in the first and second worlds. During the war, acute gouty arthritis was not common in Europe. When protein foods became abundant again every day, the incidence of arthritis returned to pre-war levels. In the past, the incidence of gout was rare in Japan, but it has become common as protein consumption in the country has increased. Clinical reports of gout have also gradually increased in China, especially since the 1980s.

Hyperuricemia is the most important biochemical basis of gout, but it is not synonymous with gout. It can only be called gout if it develops inflammatory arthritis or gout. All types of gout account for about 5% of cases of arthritis. Gout and hyperuricemia can be clinically divided into two major categories: primary and secondary. The etiology of the primary is mostly unexplained, but a few are due to enzyme defects, often accompanied by hyperlipidemia, obesity, diabetes, hypertension, arteriosclerosis and coronary heart disease. Secondary cases are caused by the large amount of nucleic acids in the nucleus of tissue cells, such as leukemia and tumor chemotherapy, or decreased uric acid excretion due to renal failure, or because various drugs such as dihydrogluuride inhibit renal tubular excretion, or Caused by a large amount of keto acid production and inhibition of uric acid excretion from the urine. In addition to the accelerated decomposition of nucleic acids to increase uric acid, most are due to reduced uric acid excretion. Classification of primary gout and hyperuricemia and secondary (Table 1).

At present, due to a deep understanding of the pathogenesis of gout, clinicians can apply many drugs with significant curative effects, such as probenecid, allopurinol, benzbromarone, and nonsteroidal anti-inflammatory drugs ( NSAID), etc.

Gout and Hyperuricemia Epidemiology

Age and gender have a significant effect on blood uric acid. The average value of men before puberty is about 3.3 mg / dl, but after puberty, the blood uric acid value of men increases faster than that of women, and then maintains a peak plateau, with a value of about 5.2 mg / dl. Increasing, the chance of gout attacks also increased thereafter, reaching a peak at the age of 50. After puberty, the blood uric acid value of women does not increase significantly, and it rises rapidly after menopause, reaching a blood uric acid value similar to that of men. This may be because estrogen can promote the excretion of uric acid in the kidneys.

Hyperuricemia patients are more obese and often combined with hypertriglyceridemia, hypertension and other factors affecting blood uric acid value include creatinine, drinking, diet and so on. Patients with hyperuricemia without gout are due to insufficient degree and duration of hyperuricemia.

The incidence of hyperuricemia varies by race and region, with 2% to 18% of indigenous populations in the South Pacific such as Nauru (Micronesian) in Europe and America as high as 64%. The prevalence of gout among indigenous people in Taiwan, China is attracting academic attention. According to a survey by Ge Yingqin (1997), the prevalence of gout among males over 40 years of age is 9.2%, and the highest incidence of gout is 31.3% in Bunun. Uric acidemia. The incidence of gout in Europe and the United States accounts for 0.13% to 0.37% of the total population, and the annual incidence is 0.20% to 0.35%.

Due to economic and food changes in Taiwan, China, the number of gout patients has increased dramatically. Chen Zhengyan found that the number of gout patients increased with the improvement of the economic level of Taiwan, China. Gout accounted for 5% of the number of rheumatology specialist clinics from 1960 to 1963, and it had reached 15.6% from 1982 to 1985. Clinical analysis of gout. Zhou Biser (1988) conducted a community epidemiological survey in Puli Township, Nantou County, and found that there are many people with hyperuricemia in the age group of over 30, with an incidence rate of 17.3%, of which 20.3% are male (sample 542) are higher than female 14.6% (616 samples). The average blood uric acid was 4.8 ± 1.8mg / dl, which was 6.4 ± 1.8mg / dl for men, which was higher than 5.2 ± 1.5mg / dl for women.

The results of epidemiological studies in Jinhu Town, Jinmen County pointed out that in young age, the risk factors of hyperuricemia are mainly hyperlipidemia, such as high triglyceride and high cholesterol. This result reflects the early hyperuricemia. Formation and eating habits are important. Once entering middle age, in addition to hyperlipidemia, hyperuricemia is significantly associated with some lifestyle habits such as drinking and obesity. In addition, clinical symptoms such as hypertension and renal dysfunction may also begin to appear in old age. The most important risk factors are the use of diuretics and the development of renal complications. Since the diuretic itself has been used as the first-line drug for the treatment of hypertension in many regions, although blood pressure has been relatively controlled, it has been replaced by an increase in blood uric acid value.

To further explore the risk factors for the evolution of hyperuricemia into gout, the second follow-up study of Jinhu Town, Jinmen County from 1996 to 1997 found that the cumulative incidence of gout in men for 5 years was 18.83%. The risk factor patterns for asymptomatic hyperuricemia to evolve into gout are as follows: First, uric acid concentration is the most important factor. For every one unit (mg / dl) of future gout, the existing uric acid concentration of asymptomatic hyperuricemia is increased. The chance of occurrence also increased by 5 times. Second, under existing conditions, blood creatinine can also predict the relative risk of gout in the future. Third, other factors such as weight gain, use of diuretics, and drinking habits may cause rapid fluctuations in blood uric acid values during the progression of hyperuricemia disease, leading to acute gout. Therefore, for asymptomatic hyperuricemia patients, we should first focus on the long-term monitoring of existing uric acid concentration and creatinine value, in addition to weight control, avoid using diuretics to treat high blood pressure, control drinking habits, etc., to prevent rapid blood uric acid value Fluctuations to avoid the occurrence of acute gout.

In addition, epidemiological studies have observed a correlation between hyperuricemia and insulin antagonist syndrome and cardiovascular disease. Scholars such as Warld HJ (1998), Lehto (1998) and Alderman MH (1999) have pointed out in their research that uric acid concentration is a very important independent risk factor for diabetes or hypertension and that the relationship between uric acid concentration and insulin resistance Relationships are directly related. Therefore, for patients with hyperuricemia, not only should gout be prevented, but further attention should be paid to the existence of insulin resistance represented by hyperuricemia to some extent. Asymptomatic hyperuricemia patients often ignore the potential harm of hyperuricemia because there are no symptoms of gout. The proportion of people suffering from various chronic diseases is often higher than that of the normal population.

Causes of gout and hyperuricemia

Hyperuricemia is a problem often encountered in clinical biochemical examinations. The daily uric acid produced by normal people can maintain a constant state of uric acid if the rate of production is equivalent to the excretion rate. Otherwise, it may cause the cause of hyperuricemia and hyperuricemia. And classification, can be roughly divided into metabolic causes of excessive type (10%) and renal causes of poor excretion (90%) (Table 2).

1. Genetic factors have been found to have a familial tendency to gout from ancient times. Among patients with primary gout, 10% to 25% have a positive family history of gout, and 15% to 25% of gout patients have hyperuricemia. Therefore, primary gout is considered to be chromosomal dominant but incomplete. The genetic condition of hyperuricemia varies greatly and may be polygenic. Many factors can affect the genetic manifestations of gout, such as age, gender, diet and renal function. Two congenital purine metabolism disorders have been identified as sex-linked inheritance, namely hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency and 5-phosphate ribose-1-pyrophosphate synthetase (PRPP synthetase) Hyperactivity type, female as carrier, male onset. In secondary gout, glycogen storage disease type (von Gierke disease) is a recessive inheritance of chromosomes. In order to determine the genetic pattern, more specific phenotypes of each type of gout must be found.

Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) is an important salvage enzyme in purine metabolism. It has the ability to catalyze the conversion of hypoxanthine or guanine to the respective nucleoside monophosphate IMP (secondary The function of xanthine nucleotides) or (3MP (guanine nucleotides), PRPP as its substrate. HGPRT provides an alternative pathway to synthesize nucleotides, this characteristic makes it in hybridoma technology Medium (using HAT culture medium) can play a role in screening viable cells; in clinical research, HGPRT is completely lacking, causing PRPP accumulation to accelerate purine synthesis, and eventually causing excessive uric acid production.

The clinical disease caused by this complete lack of HGPRT is called Lesch-Nyhan syndrome (Lesch-Nyhan syndrome), which is a sex-linked genetic disease. The illness begins in early childhood. The most typical clinical features are neurological symptoms such as self-mutilation, chorea, and insufficiency. In addition, excessive uric acid causes gout and kidney stones. Patients often suffer from infection or renal failure. The rate of premature death is about 1 in 100,000 newborns among Caucasians. This syndrome can also occur in patients whose HGPRT enzyme is still partially active. The clinical symptoms are usually gout and / or urinary uric acid stones, with or without mild neurological symptoms.

According to previous research by Lin Xiaoyi and others, HGPRT enzyme activity in red blood cells of Taiwanese in China was 1.00 to 2.20 nmol / mg protein per minute and analysis of patients and families with severe gout or abnormal neurological symptoms confirmed 3 cases of Lesch-Nyhan syndrome. The first case was a 4-year-old child with obvious self-harm behavior, chorea, and insufficiency. Urine and B-ultrasound examination showed a large amount of uric acid sodium crystals precipitated in the kidney tissue and urinary tract system, and its HG-PRT enzyme activity Completely lacking. After analyzing the family tree of the patient, it was found that all three of his uncles died of similar symptoms before the age of three. Therefore, it is presumed that this is a sexually-linked genetic disease. The patient's maternal grandmother and mother are carriers of HGPRT gene defects. The second case was a 1-year-old boy who was confirmed by yellow crystals and hyperuricemia on the diaper. His brother also confirmed the same disease due to a complete lack of HGPRT at 3 months, so it is also known as sex-linked inheritance.

The biggest breakthrough in gout research is the understanding of purine metabolic pathways, especially HGPRT enzymes. In recent years, a team of researchers led by Caskey and others at Baylor Medical Center in Houston, USA has successfully analyzed the nucleoside sequence of the 57 kb HGPRT gene in Taiwan. The case of the first case of a boy with Lesch-Nyhan syndrome in Taiwan has been confirmed as a gene dot Caused by mutation (pointmutation).

2. Related disease factors Gout is often accompanied by hypertension, hypertriglyceridemia, arteriosclerosis, coronary heart disease and type 2 diabetes (NIDDM). Among the causes of death in elderly gout patients, cardiovascular factors exceed renal insufficiency. However, there is no direct causal relationship between gout and cardiovascular disease, but both are related to obesity and dietary factors. Restricting diet or reducing weight can improve the condition. Other gout-associated diseases such as myeloproliferative disease and hemolytic anemia, chronic kidney disease, lead intoxication with beryllium beryllium poisoning, sarcoma, hyperparathyroidism, Down syndrome, and psoriasis are caused by accelerated nucleic acid decomposition. Excessive uric acid and / or decreased renal excretion of uric acid.

3. Purine metabolism and clearance factors First understand the physical and chemical properties of uric acid (Figure 1). Uric acid is trioxypurine, which is weakly acidic. Its dissociation constants (PKa) are 5.75 (the 9th nitrogen dissociation) and 10.3 (the 3rd nitrogen dissociation). The degree of dissociation is related to blood pH. The pH of human blood is 7.4, and about 98% of uric acid in serum is free uric acid ion. It can be combined with sodium to form monosodium urate. Under normal physiological conditions, human serum uric acid is about 7mg / dl. Saturated uric acid is easy to form needle-like microcrystals when it is in a supersaturated state. It is deposited in the form of gout stones in connective tissue such as articular cartilage synovium. Due to the high sodium concentration in the kidney medulla, it is easy to cause tiny tophi to settle in the renal interstitial tissue, causing inflammation of the interstitial tissue, which can lead to urate nephropathy over time.

Uric acid is the final product of human purine metabolism. There are two sources of human uric acid. They are exogenous from foods rich in purines or nucleoproteins, accounting for about 20% of uric acid in the body; they are synthesized and catabolized by nucleic acids, amino acids, nucleotides, and other small molecules in the body. It is endogenous and accounts for about 80% of total uric acid in the body. For the occurrence of hyperuricemia, endogenous metabolic disorders are more important than exogenous factors. High-purine diet can increase blood uric acid concentration, even to the extent equivalent to gout patients. Although high-purine diet is not the primary cause of gout However, a large amount of purine absorption can cause rapid changes in the extracellular fluid uric acid value, which is often the cause of acute gouty arthritis.

There are three kinds of purine nucleotides involved in uric acid metabolism: hypoxanthine nucleotide (IMP), adenine nucleotide (AMP) and guanine nucleotide (GMP). There are two pathways for its anabolic metabolism: one is the main pathway, which is biosynthesis, which synthesizes hypoxanthine nucleotide (IMP) from a non-purine-based precursor through a series of steps, and then converts adenine nucleotide (AMP) or guanine nucleotide (GMP); the second is salvage pathway, which directly synthesizes purine nucleotides from purine bases from the liver, such as adenine adenine nucleotide, hypoxanthine hypoxanthine or guanine guanine nucleotide. The rate of purine metabolism is controlled by the amount of 5-phosphate ribose-1-pyrophosphate (PRPP) and glutamine, as well as the negative feedback of guanine nucleotides, adenine nucleotides, and hypoxanthine nucleotides on the enzyme To adjust (Figure 2).

The rate of human uric acid production is mainly determined by the concentration of PRPP in cells, and PRPP synthetase, hypoxanthine-guanine phosphoribosyl transfer-ase (HGPRT), phosphoribosyl pyrophosphate Aminotransferase and xanthine oxidase are important enzymes among them, and phosphoribosyl pyrophosphate amide transferase is a rate-limiting reaction enzyme.

Studies have found that the average amount of uric acid in the uric acid pool of normal humans is 1200 mg, which produces 750 mg per day. About 2/3 are cleared by the kidneys and 1/3 are excreted by the intestines. Uric acid is mostly excreted by the kidney in the form of free sodium urate. A small part of uric acid can be destroyed. Uric acid secreted by the human intestinal tract is broken down by bacteria into allantoin and carbon dioxide. No decrease in uric acid breakdown was found in gout patients. In fact, during hyperuricemia, especially after renal failure, uric acid that enters the intestinal cavity will only increase, becoming an important second-line defense. Or) Decreased uric acid excretion is an important mechanism for the increase of serum uric acid in patients with gout.

After eating purine diet for 5 days, 90% of patients with gout were found to be of the uric acid exclusion type, but their renal function was still normal, mainly because the kidney's threshold for uric acid elimination was higher than that of normal people. The patient's blood uric acid value exceeds 1 to 2 mg / dl in normal people before a considerable amount of uric acid begins to be excreted. This defect is particularly obvious in people with normal uric acid levels. Renal excretion of uric acid depends on glomerular filtration and proximal tubular reabsorption (98%). 100%), secretion (50%) and reabsorption after secretion (40% 44%), Henle ascending branch and collecting duct can also absorb a small amount of uric acid and the final excretion accounts for 6% 12% of the filtration (Figure 3). Drug-induced hyperuricemia, such as low-dose aspirin diuretics, anti-tuberculosis drugs, or anti-rejection drugs after organ transplantation, cyclosporine A is related to the suppression of secretion. Patients drink plenty of water, maintain urine volume and alkalinize urine pH value to reduce uric acid to prevent the formation of kidney stones and sodium urate nephropathy.

Gout and Hyperuricemia Pathogenesis

1. Pathogenesis Species with urcase (uricase) can convert uric acid into allantoin, which is more soluble and easier to excrete, so the serum uric acid level is low without gout. Human (Homo sapient) and several humanoid species (hominoid species) were mutated and inactivated by the uric acid oxidase gene during evolution. From this point, human hyperuricemia is a congenital defect of uric acid catabolism. Caused. Dissolved uric acid may be beneficial to humans as a scavenger of active oxygen including peroxynitrite derived from oxygen and superoxide. Hyperuricemia serum uric acid concentration depends on the balance between the rate of uric acid production and excretion. There are two sources of uric acid in the human body. One is from the decomposition of nucleotides in nucleoprotein-rich foods, which is exogenous, accounting for about 20% of uric acid in the body; the second is from amino acids, ribose phosphate and other small molecules in the body. Compound synthesis and nucleic acid catabolism are endogenous, accounting for about 80% of total uric acid in the body. For the occurrence of hyperuricemia, it is clear that endogenous metabolic disorders are more important than exogenous factors. The nuclide tracing study shows that the average uric acid in the uric acid pool of normal human body is 1200mg, which produces about 750mg per day, and it excretes 500 1000mg. About 2/3 is excreted by the urine, and the other 1/3 is excreted by the intestine or oxidized by bacteria in the intestine Enzymatic breakdown. The serum uric acid concentration in normal people fluctuates within a narrow range. The average domestic normal male is 339µmol / L (5.7mg / dl), and the female average is 256µmol / L (4.3mg / dl). Race, diet age, and body surface area. Generally speaking, uric acid increases with age, especially in women after menopause. Men are usually higher than women, but women's blood uric acid levels can be close to men's after menopause, and clinically often exceeds the above average. Or more than two standard deviations (SD) above the normal mean of the same sex is hyperuricemia. Because gout is caused by uric acid crystals rather than dissolved uric acid, "hyperuricemia" is determined by the solubility of uric acid in body fluids rather than the statistical distribution of uric acid levels. The amount of uric acid produced per unit time exceeds the ability to remain dissolved after treatment, and monosodium urate crystals are deposited outside the cell. The temperature of the peripheral joints (about 32 ° C in the knee and about 29 ° C in the ankle) also greatly reduced the solubility of uric acid. Gout can occur if the inflammatory response is triggered again.

(1) There may be molecular defects in the mechanism that leads to excess purine biosynthesis; for example, the number or activity of purine metabolic enzymes is increased; the enzyme activity is reduced or lacking.

The number of enzymes is increased or the activity is too high:

A. Increase in number and activity of phosphoribosyl pyrophosphate amide transferase (PRPPT): This enzyme is a rate-limiting reaction enzyme that catalyzes the formation of 1-amino-5-phosphate ribose (PRA) reactions. PRPPAT increases and PRA production also increases. When the hypoxanthine nucleotide synthesis is increased, which results in an increase in uric acid production and adenylate or guanylate decrease, the inhibition of this enzyme is reduced. Increased uric acid production.

B. Increased activity of PRPP synthetase: This enzyme can promote the synthesis of nucleic acids and purine bases and increase the production of uric acid.

C. Increased xanthine oxidase (XO) activity: This enzyme can accelerate the oxidation of hypoxanthine to xanthine, and then accelerate the increase of xanthine to generate uric acid XO activity, which is not due to a congenital defect due to secondary enzyme induction in the liver.

D. Too much glutathione reductase: Too much enzyme can catalyze reduced niacinamide adenine dinucleotide (IVADPH) and oxidized glutathione (GSSG) into nicotinamide adenine diglycoside Acid phosphate (NADP) and reduced glutathione (GSH). NADP is a coenzyme of the pentose phosphate loop. When it is too much, it can promote the pentose phosphate loop and increase the synthesis of 5-phosphate ribose, which leads to an increase in ribose phosphate pyrophosphate (PRPP) and an increase in uric acid production.

reduced or lacking enzyme activity:

A. Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency: This enzyme can promote the conversion of hypoxanthine to hypoxanthine nucleotide guanine to guanylate. When HGPRT is lacking, PRPP consumption decreases and PRPP accumulation , Which increases the production of uric acid.

B. Glucose-6-phosphatase deficiency: can cause type I glycogen accumulation disease. Glucose 6-phosphate cannot be changed to glucose, metabolism shifts to gluconophosphoric acid, and part of it is converted to 5-phosphate ribose

C. Deficiency of glutaminase: Deficiency of this enzyme reduces the degradation of glutamine, stores glutamine, and increases the matrix for purine base synthesis.

D. Low glutamic acid dehydrogenase activity: It can reduce the dehydrogenation of glutamic acid to -ketoglutarate and increase the amount of glutamine, which increases the synthesis of purine and uric acid.

The main cause of hyperuricemia is excessive uric acid production, accounting for 70% to 80% of those with low uric acid excretion, accounting for only 25%. Most patients with primary hyperuricemia have a 24-hour uric acid excretion within the normal range. 20% to 25% of patients excrete more patients with increased uric acid excretion, and abnormal purine synthesis; and normal uric acid excretion in urine Of the patients, 2/3 patients also had excessive renal excretion of purine, which depended on glomerular filtration for proximal renal tubular reabsorption (98% -100%), secretion (50%), and reabsorption after secretion (40% 44%). Reduced glomerular filtration, increased reabsorption of urate by the renal tubules, or decreased urate excretion by the renal tubules can cause hyperuricemia

(2) Mechanism of uric acid production and clearance: The total uric acid pool in the whole body, which can communicate with sodium urate in plasma, is determined by the rate of uric acid production and disposal, and it expands in gout (Table 3A B). Xanthine oxidase acts on the substrate purine bases hypoxanthine and xanthine to produce uric acid. Most of the purines in the diet are degraded into uric acid by degrading enzymes (including xanthine oxidase) in the intestinal epithelium. Restricting purine intake can slightly lower serum uric acid levels (0.6 to 1.8 mg / dl), but the difference in absorption has no effect on the occurrence of hyperuricemia. Most uric acid is caused by hepatic xanthine oxidase. Xanthine and xanthine produce nucleic acid from senescent cells and cellular purine nucleotide metabolism renewal, the latter has two biosynthetic pathways, namely "recovery" ("reuse") and "new synthesis" (Figure 4 ).

Most uric acid is cleared by the kidneys. When about one third of the urinary dysfunction is degraded by bacteria in the intestine, the degradation of uric acid by bacteria is significantly increased. Uricosuric agents that promote increased uric acid excretion in the urine block the recovery of uric acid, while other drugs and weak organic acids inhibit the secretion of uric acid by the kidneys and increase serum uric acid levels. Hyperuricemia during fasting, alcohol metabolism, and ketoacidosis is due to the latter mechanism.

Intracellular Purine Metabolism and "Metabolic" Hyperuricemia Pathways In the "new synthesis" pathway, the purine ring (hypoxanthine) of hypoinosine (inosinic acid) (IMP) is formed from a precursor on the ribose-5-phosphate backbone derived from phosphoribosyl pyrophosphate (PPRP). This pathway separately produces adenylate (adenosine-phosphate) (AMP) and guanylate (guanosine-phosphate) (GMP) and their derivatives at IMP. In the "remedy" pathway, prepurinyl hypoxanthines, guanines, and adenines (from IMP, GMP, and AMP) undergo hypoxanthine transphosphoribosylase (HPRT,) and adenine transphosphoribosylase (APRT) ), Directly condense with PP-ribose-P, and then generate these ribonucleotides. Some hypoxanthines formed by nucleotide renewal enter the liver, and are broken down by xanthine oxidase (XO) into uric acid, and the rest are processed by HPRT.

The remedial pathway (more economical in terms of energy requirements) can reduce renewal synthesis activity because (1) HPRT and APRr have a higher affinity for PP-ribose-P than amide ribosyltransferase (amide PRT).

The lack of HPRT inevitably results in the loss of all hypoxanthines and guanines as uric acid. At the same time, the reduction of inhibitory nucleotide formation and the increase in the concentration of PP-ribose-P that can be used for amide PRT reactions also make modern synthetic pathways compensatory increase. Inherited PP-ribose-P synthase "hyperactive" mutant individuals, increased PP-ribose-P formation, stimulated the amide PRT and resulted in a substantial increase in purine neosynthesis.

Increased nucleotide decomposition can increase blood uric acid levels due to increased XO substrate production and inhibition of amide PRT release. Hyperuricemia and gout in the absence of glucose-6-phosphatase (type 1 glycogenopathy), which is related to this mechanism: glucose-6-phosphate is accumulated at the expense of hepatic gland triphosphate (ATP), AMP is degraded to uric acid. Conditions that can decompose nucleotides, such as hypoxia, metabolism of certain sugars, vigorous exercise in normal people, and moderate exercise in patients with metabolic myopathy may rapidly increase blood uric acid. (5NT = 5 mononucleotide enzyme; PNP = purine nucleotide phosphorylase; ADA = adenosine deaminase; AK = adenosine kinase)

(3) The mechanism of hyperuricemia: There is evidence that about 10% of gout patients have too much uric acid production, that is, uric acid excretion in urine exceeds the normal value + 2 SD (that is, when purine diet is restricted> 600 mg, normal diet> 800 mg). The two most common genetic defects in the regulation of purine nucleotide synthesis are the lack of the remedial enzyme hypoxanthine-guanine phosphoribosyltransferase deficiency and phosphoribosyl pyrophosphate synthase ( phosphoribosyl pyrophosphate synthetase) hyperactivity.

Uric acid, trioxopurine, is a product of the body's purine metabolism. Under normal circumstances, most of uric acid exists in the form of sodium urate in the blood. At 37 ° C and pH 7.4, uric acid is in a deep solution state and is free in the blood. Uric acid is mainly excreted by the kidneys. The body maintains blood uric acid in a certain range through dynamic balance. The male does not exceed 417 µmol / L (7mg / dl), and the female does not exceed 357 µmol / L (6mg / dl).

Most of the causes of primary gout are unknown. About 90% of the direct mechanisms are related to the decline in renal excretion. Very few gouts in children and adolescence are genetically related. Those with a clear pathogenesis are called secondary gout, such as Lesch-Nyhan syndrome and von Gieke disease. The interaction of genetic factors and environmental factors determines the formation of hyperuricemia, and 20% of first-degree relatives of gout patients have hyperuricemia.

Most patients with idiopathic gout have normal renal function, but due to reduced uric acid excretion, increased blood uric acid levels (hyperuricemia), why this has not been found can be explained. Urinary acid excretion decreases with renal dysfunction, but gout is rare in people with chronic renal failure. In several families, early-onset hyperuricemia, gout, and progressive renal failure (sometimes accompanied by hypertension) have been reported to be interrelated (Table 1). Chronic lead toxic nephropathy, alcoholism and diuretics, and certain other drugs can cause hyperuricemia and gout due to the mechanisms of the kidney. Patients with heart and kidney transplants may develop severe hyperuricemia due to the application of cyclosporine and quickly develop gout.

Hyperuricemia and idiopathic gout are associated with obesity and hypertriglyceridemia. Some gout patients can eliminate changes such as hypertriacylglycerol, hyperuricemia, excessive uric acid production, and renal clearance disorders due to weight loss and alcohol withdrawal.

Acute gout attack mechanism: Neutrophils are the necessary medium for acute inflammation during gout (Figure 5). After neutrophil phagocytes monosodium urate crystals, 1eukotrienes interleukin-1 and glycoprotein "crystal chemotactic factor" are released, making neutrophil infiltration into the affected joint more For intensification. Activated neutrophils can also produce superoxide and release lysosomal enzymes due to lysosomal membrane rupture and cell lysis. Complement peptides and kinins are cleaved by the precursors, causing pain, vasodilation, and increased permeability. Like the prostaglandin, collagenase produced by the released lysosomes and cytosolic enzymes to joint mesenchymal cells causes chronic joint destruction and tissue necrosis.

A. Asymptomatic arthritis in gout patients: Uric acid crystals are often found outside the cells. The onset and termination may be caused by plasma proteins. They are selectively adsorbed on the crystals, which can affect their interaction with neutrophils. In the early stages of the attack, IgG antibodies produced using monosodium urate crystals as antigens can act as nucleating agents. Promote the crystallization of monosodium urate, and increase the phagocytosis of these crystals by neutrophils, thereby promoting the release of lysosomal enzymes. In the late stage of the attack, lipoproteins containing apoprotein B (apoprotein B) enter the inflamed joints from the plasma and are coated with monosodium urate crystals; this effect has effects on phagocytosis, neutrophil oxidative metabolism, superoxide generation and cytolysis, etc. All have inhibitory effects. The differences in the quality and quantity of protein regulators can explain the difference in the inflammatory response to uric acid crystals in gout and non-gout.

B. Acute gouty arthritis: sodium urate forms microcrystalline precipitates in joints and tissues around joints, causing non-specific arthritis is a complex process and may be the result of a combination of factors. The solubility of urate is pH 7.0 under normal physiological conditions, and it is 381 µmol / L (6.4 mg / dl) at a temperature of 37 ° C. If it exceeds this concentration, it will reach a supersaturated state. Because there are fewer articular cartilage, synovial tissue, and tissues around the joint, the matrix contains mucopolysaccharide acid and connective tissue. When the urate in the body fluid reaches a supersaturated state, under certain induced conditions, such as injury, local When the temperature is lowered, the local pH value is lowered, or general fatigue, alcoholism, or urate is easily crystallized when the combination of urate and urate decreases due to the decrease of plasma 12 globulin. Crystals of urate can chemowhite blood cells. Leukocytes and synovial cells in the joint capsule can release leukotriene B4 (LTB4) and glycoprotein chemotactic factor urate crystals within a few minutes after phagocytosis of urate can be adhered to the surface of crystals IgG on the surface of the crystal can enhance the phagocytosis of leukocytes, and some specific proteins such as LDL can inhibit this effect. The above phenomenon can explain the inconsistent inflammatory response caused by urate crystals in patients with gout. In vitro tests have shown that monocytes can release interleukin-1 (IL-1) after being stimulated by urate crystals. IL-1 can cause gout and Makes inflammation worse. It has been reported that other cytokines such as IL-8, TNF, and the complement system also participate in the above-mentioned inflammatory response, but not each of the above factors is necessary. After urate crystals are engulfed by cells, leukocytes quickly degranulate and decompose, destroying the lysosomal membrane and releasing hydrolytic enzymes, causing leukocyte necrosis to release a variety of inflammatory factors, such as kallikrein, leading to the onset and exacerbation of acute inflammation. Cholesterol and testosterone are sensitive to the cytolytic response caused by urate. If -estradiol is included, the above reactions are inhibited, so gout is more common in men and postmenopausal women, especially the lower extremity joints: the toe joint is under the most stress. It is easy to be damaged, and the local temperature is low, so it is a good place for gout. Acute gouty arthritis is self-limiting and may be related to the following factors: a. Local temperature increases during the onset of inflammation, uric acid dissolution increases, and newly formed crystals decrease. b. Increased local blood flow, urate is absorbed into the bloodstream. c. The swallowed urate can be destroyed by the medulla peroxidase of white blood cells, reducing the amount of urate released when white blood cells rupture. d. Stress of inflammation excites the adrenal cortex, increases hormone secretion, and inhibits the inflammatory process. Rapid fluctuations in blood uric acid can cause acute gouty arthritis. If the sudden decrease in blood uric acid, the tonic stones in the joint can be dissolved to release insoluble needle-like crystals. This can explain why gout patients have acute gouty arthritis when they use uric acid drugs and drugs that inhibit uric acid production.

The mechanism of tophus: tophus (tophus) is the deposition of needle-shaped fine crystals of monosodium urate, surrounded by chronic mononuclear cell reactions and foreign body granulomas of epithelial cells and giant cells, which may be multi-core tophus that is common in joints

(punchedout lesions)

90%3

A.Henle

B.20%40%89%()pHpH 5.085%100ml15mlpH 7.010pH8.0100

C.

(urate nephropathy)()

10%25%200700mg20%(5012A)1100mg50%12mg/dL50%80%()

PHpH 53715mg/dLpH 710pH 8100

(4)3

2.Lesch-Nyhan

4520:1X-4(678)

1.416µmol/L(7mg/dl)

2.190%(9)75%90%

11162%116%1211%254%5107%

3.(1011)

(1)(121314)10

(2)472µmol/L(8mg/dl)90%531µmol/L(9mg/dl)50%(151617)

(3)3

17%25%

20%25%24h1/3X

4060mg/dl

(4)

(5)

(6)1%2

(von Gierke)

A.6-

B.

C.

D.10

Lesch-Nyhan-(HGPRT)16881020%-

(NIDDM)

Middle-aged and elderly men suddenly and repeatedly experience lower joints such as the iliac crest, ankle, and knee with single joint redness, swelling, and pain with an increase in blood uric acid, that is, the possibility of gout should be considered. Joint pain and inflammation have a rapid response to colchicine treatment and are characteristically diagnostic. The diagnosis can be confirmed if typical needle-shaped birefringent uric acid crystals are found in leukocytes in the bursal fluid, or urate crystals are deposited on microscopic examination.

1. Sudden severe arthritis of peripheral joints, especially when it occurs in the joints of the lower extremities, it should be thought that if there is a history of fractional attacks of gout (no symptoms during non-seizures), it can also help diagnosis. Polarized light microscopy revealed that white blood cells in synovial fluid had shiny negative birefringent uric acid monosodium needle needle crystals to confirm the diagnosis. The number of white blood cells in synovial fluid ranges from 5,000 to 50,000 / mm3 or more, depending on the acute degree of inflammation. The synovial fluid should also be stained with Gram and cultured as it may be accompanied by infection.

2. It is meaningful to measure uric acid excretion in 24h urine, especially in the face of young patients with significant hyperuricemia suspected of metabolic etiology. Urine samples should be collected during the non-seizure period after 3 days of moderate restriction of purine intake. In this case, if the measured discharge is above 600mg / 1.72m2 / d, it means that the uric acid is generated too much. If the daily discharge is more than 800mg, the specific subtype of primary or secondary gout must be examined in depth. Such as hypoxanthine guanine transphosphoribosylase (HGPRT) deficiency or phosphoribosyl pyrophosphate synthase activity; the latter such as myeloproliferative lesions. Increased uric acid excretion in the urine also increases the risk of kidney stones. Gout in these patients should be treated with allopurinol rather than uric acid-stimulating drugs.

3. Diagnostic criteria

(1) 1977 American Rheumatology Association Acute Gouty Arthritis Classification Standard (Table 4).

(2) Holmes standard of 1985: Have one of the following: leukocytes in the bursal fluid have phagocytosis of urate crystals; a large amount of urate crystals are found in the puncture of joint cavity fluid or nodule biopsy; Patients with acute arthritis, asymptomatic intermittent hyperuricemia, and effective for colchicine treatment

There are no clear diagnostic criteria for gout chronic arthritis and gout nephropathy, and most of them occur after persistent hyperuricemia and recurrent episodes of acute arthritis, and it is not difficult to diagnose in combination with related clinical manifestations and auxiliary examinations.

Differential diagnosis:

Due to the diverse clinical manifestations of gout patients, sometimes the symptoms are not typical, the following differential diagnosis must be made:

1. If only hyperuricemia is found during the asymptomatic phase, secondary hyperuricemia must be ruled out, and a detailed history should be asked to exclude various drug factors, such as thiazide drugs, itanilic acid (diuretic acid), Fasting urine, acetazolamide (acetazamide), and low-dose aspirin can all increase blood uric acid. Careful observation of clinical manifestations, combined with relevant laboratory tests, is often helpful for the presence of hypertension, cardiovascular disease, kidney disease, blood disease, and lead poisoning. In order to determine whether there is too much uric acid synthesis, the uric acid content in the urine can be measured for 24 hours after the low-purine diet for 3 to 6 days, and compared before and after the experiment. Under normal low-purine diet conditions, normal Chinese people have a 24-hour uric acid excretion of 210-600 mg, such as those with elevated blood uric acid and high urine excretion before and after the experiment, suggesting an increase in synthesis. At the same time, the ratio of uric acid and creatinine excretion can also be measured. In the case of no or low purine diet, the increase in uric acid synthesis is greater than this value. Those who are known to have increased uric acid synthesis should further find the cause of increased uric acid synthesis, such as increased blood uric acid and decreased or normal uric acid at 24 hours, which may be difficult to excrete. Further investigation of renal function should be performed to determine the cause. In addition to creatinine and creatinine, creatinine clearance should be measured, phenol red excretion test and urine specific gravity should be measured to determine the glomerular and renal tubular function status, respectively. Sometimes there is only hyperuricemia without other symptoms, and follow-up observation should be performed.

2. The following types of arthritis should be excluded in the acute arthritis phase:

(1) Acute rheumatoid arthritis: typical manifestation is migratory polyarthritis, which mainly involves large joints such as knees, ankles, shoulders, wrists, elbows and hips, often accompanied by rheumatic fever, skin and heart performance . Serum hemolytic streptococcal antibodies (including ASO> 500U anti-streptococcal kinase> 80U anti-hyaluronidase> 128U) were determined to increase C-reactive protein, multiple positive blood uric acid was not high, and salicylic acid preparations were effective.

(2) Purulent arthritis and traumatic arthritis: Gout is often easy to be confused with purulent or traumatic arthritis, but the latter two are not high in blood uric acid. There is no sodium uric acid crystal in the leukocytes of the bursal fluid examination. Traumatic Arthritis has a history of severe injuries, and pyogenic arthritis bursal fluid culture can cultivate pathogenic bacteria.

(3) Pseudogout: caused by the deposition of calcium pyrophosphate on articular cartilage. Most of them are seen in the elderly with knee joint involvement most often, which resembles gout but with normal uric acid in acute episodes. The joint bursal fluid contains calcium pyrophosphate crystals or apatite X-ray films showing cartilage calcification.

(4) other arthritis: such as lupus erythematosus is more common in young women, blood uric acid is normal. Rett syndrome is more common in men and is generally not accompanied by increased uric acid, but with conjunctivitis and urethritis.

3. Differential diagnosis of chronic arthritis

(1) Rheumatoid arthritis: It is more common in young women and occurs in the proximal interphalangeal joints of the hands and feet and the joints of the wrist, knee, and ankle. It is generally polyarticular and symmetrical. However, blood uric acid is not high, rheumatoid factor is positive, X-ray films show that the articular surface is rough, joint space is narrow, and even articular surface fusion and osteoporosis are significantly different from gouty bone defects.

(2) Psoriatic arthritis: often involves asymmetry in the distal interphalangeal joints with severe joint damage, widened joint space, bone resorption at the toe (finger) end, and sacroiliac joints are often involved, and the clinical manifestations are similar. Rheumatoid Arthritis. About 20% of patients have an increase in serum uric acid and gout, but skin lesions can be identified. Sometimes coexisting with gout is more difficult to identify.

(3) Tuberculosis allergic arthritis: The common primary tuberculosis lesions caused by tuberculosis infection are mostly located in the lungs, followed by the symptoms of poisoning such as weight loss, night sweats, and fatigue in lymph nodes. Presented as migratory polyarthralgia, with a history of acute arthritis or chronic arthralgia, but without joint ankylosing. It usually starts from the small joint and gradually spreads to the large joint. The susceptible joints include fingers, wrists, knees, ankles, shoulders, and lumbar spine. There are often nodular erythema around the joints and on the skin of both calves. The laboratory test was highly positive for the tuberculin test, and the ASO rheumatoid factor and C-reactive protein were negative. The anti-tuberculosis treatment was effective.

(4) Other chronic joint diseases include hypertrophic arthropathy, post-traumatic and sequelae of purulent arthritis. Increased blood uric acid and other factors can help diagnosis.

Gout and Hyperuricemia Examination

Laboratory inspection:

1. Blood routine and erythrocyte sedimentation during acute arthritis, there may be leukocytosis, erythrocyte sedimentation rate but often less than 60mm / h.

2. Patients with a long course of routine urine may have proteinuria, hematuria, and pyuria, and occasionally cast urine.

3. Serum uric acid determination The serum uric acid of most patients with acute attack was increased. Using uric acid oxidase method, 416 mol / L (7 mg / dl) for men and 357 mol / L (6 mg / dl) for women have diagnostic value. If uric acid drugs or glucocorticoids have been used, blood uric acid levels may not be high and the remission period may be normal

4. Uric acid measurement is not very helpful in the diagnosis of acute arthritis, because more than half of the patients with gout have normal uric acid excretion. However, understanding of uric acid excretion through urinalysis helps to select drugs and identify whether uric acid stones are caused by increased uric acid. The normal dietary male adult excreted 24 hours of uric acid at 3.54mmol (600mg / 24h urine).

Other auxiliary inspections:

1. Bursal fluid examination In the acute arthritis phase, bursal fluid from large joints such as the knee joint can be taken for polarized light microscopy. If there are birefringent needle-shaped sodium urate crystals in the white blood cells, it has diagnostic significance. The positive rate of optical microscopy is only half that of polarized light microscopy. The white blood cell count of the bursal fluid is generally between 1000 and 7000 / mm3, and up to 50,000 / mm3, which are mainly lobulated multinucleated granulocytes (Figures 18, 19, 20, 21).

2. Early X-ray examination showed local soft tissue swelling around the joints. When the disease gradually progressed to the stage of polyarticular gouty arthritis, the articular surfaces of the small joints of the hands and feet may appear several millimeters to 2 cm in diameter, with sharp edges and clear boundaries. Generally, the bone structure and density around the bone defect area of cystic puncture or worm-like bone defects were unchanged (Figures 22 to 34). In the chronic arthritis stage, due to the large amount of urate deposited on the osteoarticular cartilage, cystic lesions appeared in the subchondral joint cortex, which can form sharp round, semi-circular or lobular bone defect areas, and even Honeycomb changes can occur. Sometimes the soft tissue surrounding the gout nodules is swollen in nodules, and may have degeneration and calcification, showing dense shadows of uneven density. After the joint is damaged, degenerative osteoarthritis can eventually occur, with joint subluxation or ankylosis.

3. Special examination of tophnia. Toustone can be identified by viable biopsy or special chemical experiment (Murexide test). It can also be determined by ultraviolet spectrophotometer or decomposition by urate oxidase.

4. X-ray Dual Energy Bone Density (DEXA) Examination of Gouty Arthritis When the early X-rays have not changed, bone density has changed, and this change is related to the condition. Therefore, DEXA measurement has certain auxiliary diagnostic value for gouty arthritis.

Gout and Hyperuricemia Treatment

At present, there are still no curative drugs for gout. The clinical treatment requirements are to achieve the following 4 goals: to terminate the acute arthritis attack as soon as possible; to prevent the recurrence of arthritis; to correct hyperuricemia and prevent urate deposits in the kidneys, joints and other causes Complications; specific treatment measures to prevent the formation of uric acid kidney stones should be determined according to the stage of disease development.

1. General treatment to control diet, prevent obesity, avoid eating high purine foods, such as animal viscera (brain, liver and kidney), bone marrow, seafood crabs and other purine-rich sources; fish and shrimp, meat, peas and spinach also contain certain Amount of purine. Obese patients must limit total caloric intake to gradually reach or approach the ideal weight but not to reduce weight too quickly. Due to the rapid decomposition of fat and other tissues, it can cause increased blood ketone bodies and lactic acid concentrations, inhibit uric acid excretion, and even induce gout attacks. . In general, a moderate protein and low-fat diet is ideal. Drink plenty of water on weekdays, so that the daily urine output is not less than 2000ml, which is conducive to uric acid excretion. Gout patients' families should be screened in order to detect asymptomatic hyperuricemia early and follow up and review regularly. Avoid excessive strain, alcohol, cold, wetness, joint damage, and use of drugs that prevent uric acid excretion.

2. Patients in the acute phase should rest in bed to raise the affected limb. Generally, they should rest until the joint pain is relieved for 72 hours. A local hot compress or external application of Sansheng San to the affected joints can relieve inflammation and relieve pain. The earlier the drug treatment, the better. Early treatment can relieve symptoms quickly. Delayed treatment can reduce the effect and make inflammation difficult to control. Commonly used drugs are colchicine, non-steroidal anti-inflammatory drugs and glucocorticoids. The specific drugs are as follows (Table 5):

(1) Colchicine: It is effective for oral administration of 0.5mg or 2h 1mg per hour when it is effective for the initial use of the disease, and it will be stopped when the symptoms are relieved or gastrointestinal reactions such as nausea, vomiting, abdominal pain and diarrhea occur. Generally, 4 to 8 mg is needed. The symptoms can be relieved within 6 to 12 hours and controlled within 24 to 48 hours. After that, a maintenance amount of 0.5 mg can be given 2 to 3 times / day. Those with severe gastrointestinal tract reactions can dissolve 1 ~ 2mg of this medicine injection in 20ml physiological saline slowly and intravenously within 5 ~ 10min, but care should be taken not to leak the medicine solution according to the needs of the disease, and it can be injected again after 6 ~ 8h . In one episode, the total amount should not exceed 4 to 5 mg. For those with impaired renal function, the initial 24 hours should not exceed 3 mg. Due to the relatively small gastrointestinal response of this drug intravenously, one should be alert to toxic reactions including leukocytopenia, thrombocytopenia, anemia and liver damage caused by hair loss and bone marrow suppression. Gastrointestinal reactions often occur when symptoms are relieved. If diarrhea occurs, take 1 to 4 ml of compound camphor tincture until diarrhea stops. This medicine can cause fertility defects and should be avoided in the first 3 months of pregnancy. The pharmacological effects of colchicine may be the inhibition of chemotaxis of white blood cells and phagocytosis of urate crystals, and the release of lysosomal and lactic acid. Due to the significant clinical efficacy of this drug, experimental treatment can sometimes be performed for cases with difficult diagnosis to help differential diagnosis

(2) Non-steroidal anti-inflammatory drugs: When the diagnosis of gout is positive, non-steroidal anti-inflammatory drugs are often used to stop the acute onset of arthritis.

Indomethacin: The most widely used. The initial dose is 25 to 50 mg, once every 8 hours. After the symptoms are alleviated, it is changed to 25 mg, 2 to 3 times / d for 3 days. Side effects include gastrointestinal reactions, dizziness, rash, and sodium and sodium retention. Disable patients with active peptic ulcer.

Baotaisong: It has obvious anti-inflammatory effects, and can promote the excretion of urate in the kidney, which is still effective for those who have been affected for several days. The initial dose is 0.2 to 0.4 g, and every 4 to 6 hours thereafter, 0.1 to 0.2 g. After the symptoms have improved, it is reduced to 0.1 g 3 times per day. For 3 days, this medicine is used when colchicine has unacceptable side effects or is ineffective. Applicable.

Others: Such as hydroxybutzone (hydroxybutazone), ibuprofen, piroxicam (indomethacin), naproxen, etc., all have a certain effect in the treatment of acute gout. At the beginning of treatment, the entire treatment amount was given until the clinical symptoms were significantly improved, and then the dose was reduced to complete withdrawal. Aspirin dose is too small to have hysteretic acid effect, daily dosage of more than 4g to have uric acid effect, but easy to poison, most patients can not tolerate this dose.

(3) ACTH and prednisone: When the condition is severe and the treatment with colchicine is ineffective, 25 mg of ACTH can be added to the glucose solution for intravenous infusion, or 40 to 80 mg of intramuscular injection can also be given to prednisone 30 mg per day The oral administration lasts 2 to 3 days. This group of drugs has a rapid effect, but it is easy to "rebound" after stopping. In clinical practice, 0.5mg of colchicine is often added 2 to 3 times per day to prevent "bounce" lesions confined to a single joint. Cortisone (cortisone acetate) 25-50mg can be used as a local injection in the joint cavity. Pain is usually completely relieved within 12 to 24 hours.

3. Intermittent and chronic treatments In order to prevent acute attacks of gout and prevent the occurrence of various complications, active treatment is still needed at this stage. Colchicine is very effective in controlling the acute inflammation of gout, but it does not decrease the blood uric acid concentration or increase the uric acid excretion. Dietary control alone can only reduce blood uric acid by about 59 mol / L (1 mg / dl). Therefore, anti-hyperuricemia drugs must be used to reduce and maintain blood uric acid concentration below 378 mol / L (6.4 mg / dl) in the inter-episodic and chronic phases to prevent the formation of gout stones and reduce kidney damage.

Indications for lowering blood uric acid treatment: those whose blood uric acid concentration is still above 416 472µmol / L (7 8mg / dl) through diet control; those who have X-ray evidence of tophi or sodium uric acid deposit; annual acute attacks Those who have more than two times; those who can't control the joint symptoms continuously; those who have impaired renal function. There are two types of drugs that lower blood uric acid: promote uric acid excretion and inhibit uric acid synthesis. Both drugs have no anti-inflammatory and analgesic effects and mobilize uric acid into the blood circulation during use, which may induce the occurrence of acute arthritis, so they should not be applied in the acute phase. In choosing which type of drug, the uric acid excretion is usually less than 600 mg per day and the uric acid excretion of 24 hours is determined according to the patient's renal function. Those who have good renal function should use uric acid medicines more frequently. Drugs that can inhibit uric acid synthesis can be used; if the patient has a significant increase in blood uric acid and a large amount of goutstones are deposited, they can also be used in combination, which can reduce blood uric acid and accelerate the resolution of goutstones. Because uric acid can increase the excretion of allopurinol and its metabolites, the latter should also be appropriately increased when used in combination.

(1) Uric acid drugs: currently the following three are commonly used:

Probenecid: It mainly inhibits reabsorption of uric acid by renal tubules and increases uric acid excretion. In order to prevent the kidney damage and side effects of kidney stones caused by the large amount of uric acid excreted from the kidney, this medicine should be started from a small dose, 0.5g / d in two oral doses, and gradually increased to (1 1.5g) / d in two weeks. 3 to 4 times orally with a maximum dose of 3 g / d can only be increased to this dose if the effect is not significant after 2 to 3 months of trial. But prone to gastrointestinal reactions, rashes, headaches and drug fever. If the above-mentioned side effects occur, timely application of sulfopyrone.

Sulpyrone: It is a derivative of Baotaisong, which inhibits the reabsorption of uric acid by the renal tubules. The effect of uric acid is stronger than probenecid. It also starts at a small dose, 100mg / d, and is taken orally twice, and gradually gradually after 10 days. Increase to 300-400mg / d, orally divided into 3 to 4 times, the maximum daily dose is 600mg. This product also has gastric mucosal irritation, and those with peptic ulcer should be used with caution.

benzbromarone: a powerful diuretic acid is particularly suitable for those who should not use probenecid and allopurinol or have extensive gout nodules. Usage is 25 100mg, once / d. Side effects include gastrointestinal reactions, rashes, fever, renal colic, and acute attacks of gout. The total effective rate of this medicine in treating gout in China is 89%.

During the treatment of uric acid drugs, sodium bicarbonate should be taken orally in the range of 3-6 g / d to alkalinize the urine and drink plenty of water to maintain a daily urine volume of more than 3000ml to facilitate uric acid excretion.

(2) Allopurinol: This medicine can inhibit xanthinase, make hypoxanthine and xanthine unable to be converted into uric acid, and also inhibit the biosynthesis of purine. For uric acid synthesis, hyperuricemia, ineffective or allergic to uric acid drugs, repeated formation of renal uric acid stones or renal failure, and before and after chemotherapy for myeloproliferative diseases. 100 mg each time, 2 to 3 times per day, can be increased to 200 mg each time, 3 to 4 times per day. Combined with uric acid drugs can enhance the efficacy, but generally do not need to be combined. Individual patients may have fever, rash, abdominal pain, diarrhea, leukocytes and thrombocytopenia, and may even have side effects such as hepatomegaly and liver damage. There may also be uric acid transfer gout attacks during treatment, which can be supplemented with colchicine treatment.

(3) Preventive medication: For patients with recurrent gout, chronic inflammation is not easy to control, and sometimes there is still an acute attack of arthritis, especially in the early stage of treatment with uric acid drugs and allopurinol. At this time, it can be maintained with a small dose of colchicine, 0.5 1mg / d, often can control symptoms, can also be applied indomethacin (indomethacin) 25-50mg / d maintenance treatment.

(4) Treatment of asymptomatic hyperuricemia: opinions differ from each other. It is generally considered that no treatment is needed. But should avoid obesity, overeating and drinking and mental stress and other factors that can cause acute gout. It has also been suggested that if the blood uric acid concentration exceeds 476 to 535 µmol / L, especially those with a low family urinary excretion and a positive family history should be treated with allopurinol and follow-up to observe the development of the condition.

(5) Symptomatic treatment: For those with complications such as hypertension, coronary heart disease, diabetic obesity, kidney stones, urinary tract infections, and renal failure, symptomatic treatment is required. Those with joint difficulties will be given physical therapy and functional exercises. Tophus rupture to form a fistula should be surgically scraped.

(6) Treatment of secondary gout: In addition to the treatment of the primary disease, the treatment principles for gout are the same as those described above for lowering blood uric acid. Allopurinol should be selected. Those with renal dysfunction should appropriately reduce the dosage. It is feasible for severe kidney injury Dialysis treatment. Uric acid drugs can easily increase the burden on the kidney and should not be used.

4. Chinese medicine treatment

(1) Dialectical treatment:

Wind cold dampness:

Symptoms: limb or joint pain or migraine pain, or severe joint pain, soreness, or severe swelling and pain in the limbs and joints, numbness of the skin in rainy days aggravated by thin white tongue coating, tight or slow pulse strings.

Governing Law: Qufengsanhan, dehumidification Tongluo.

Recipe: Coix Seed Decoction. Fang Zhongzhu live, lone live windproof Qufeng win dampness; Chuanwu, Ephedra, Guizhi warm and scattered cold; Coix kernel, Atractylodes spleen and dehumidify; Angelica, Chuanxiong nourish and promote blood circulation; Ginger, licorice and spleen.

Rheumatic fever:

Symptoms: Redness, swelling, hot and painful joints, untouchable pain, coldness is more acute, accompanied by fever, thirst, irritability, sweating, red tongue, yellow tongue fur, slippery pulses.

Governing Law: clearing heat and clearing collaterals, eliminating wind and dampness

Recipe: White Tiger and Guizhi Decoction. Fang Zhongsheng gypsum, Zhimu, licorice, and japonica remove heat and remove annoyance;

Phlegm and Stasis Obstruction:

Symptoms: Bi syndrome persists for a long time, recurrent attacks, joint pain is mild and severe, joint swelling, even tonic deformity, unfavorable flexion and extension, subcutaneous nodules, pale tongue or ecchymosis, white tongue, greasy tongue, thin pulse .

Governance: Huatan Quyu search wind Tongluo.

Recipe: Taohong drink with flavor. Fangzhong Taoren Honghua promotes blood circulation and stasis; Angelica tail, Chuanxiong nourishes blood and promotes blood circulation; Wei Lingxian passes through the twelve meridians, which can guide and declare, and dispel wind and dampness.

If there are subcutaneous nodules, add white mustard seeds 10 20g, stiff silkworms 5 10g to expel sputum; and sputum retention patients add insecticides, such as 5-10g black snake, 3 5g of whole scorpion. Remove stasis and search for wind.

Liver and kidney loss:

Symptoms: long-term paralysis, recurrent episodes, or migratory pain or severe soreness, and even joint deformity is unfavorable, paralyzed lumbar spine pain, fatigue, shortness of breath, spontaneous sweating, complexion, pale tongue, The pulse is thin or weak.

Governing Law: Tonify liver and kidney, expel wind and dispel cold and dehumidify.

Recipe: Duhuo Parasitic Decoction. Fang Zhongshu Dihuang, Eucommia ulmoides, Achyranthes bidentata replenishes liver and kidney, strengthens bones and bones; Ginseng Poria, licorice replenishes qi and strengthens spleen; Angelica sinensis, Chuanxiong, Shaoxing Yangxue and camp; solitary living, windproof, Qinjing, Asarum, Guizhi expelling wind Scatter cold, dehumidify and palsy.

(2) Comprehensive treatment:

Chinese patent medicine: Fengbi dampness type can choose Xubi granules and Qufengshujin pill; rheumatic heat type can choose Shimiao Pills plus flavored Hexin tincture tablets, Ruyi golden powder; Shutan Huoxue tablets can be chosen for sputum obstruction type , Wan; liver and kidney loss type can choose Guifu Dihuang Wan, Yishen Zhibi Pill.

Single prescription:

A. Tripterygium wilfordii Root peeled 15g raw licorice 5g, Jianshui take 1 dose per day, 14 days as a course of treatment, suitable for wind cold dampness type.

B. 15g each of yarrow and stinky sycamore, take decoction, 1 dose per day, 1 course for 14 days, suitable for wind cold dampness type.

C. Acupuncture therapy: General acupuncture should be used in combination with wind coldness and dampness; acupuncture should be used in combination with wind coldness and coldness; acupuncture should not be used in moxibustion; Yangchi, Waiguan, Hegu; elbow pain from Hegu Shousanli, Quchi; knee pain from knee eyes, Yanglingquan; ankle pain from Zhongfeng, Kunlun, Jiexi, Qiuxu, etc.

Fang 1: Ankle area on both sides of the spine, limbs, and localized dorsum of the foot, focus on lumbosacral spine and its sides

Governing Law: Adopt positive puncture and heavy puncture. First stab the spine and the sides 3 times 1 to 2 times, and then focus on stimulating the lumbosacral vertebrae and the sides 5 times, 5 times each, and then perform local stimulation on the limbs, dorsal region, and ankle joint areas once daily, 10 1 course of treatment

Square 2: sides of spine, lower abdomen, diseased limbs, joints, focus on lumbosacral and its sides

Governing Law: Adopt positive thorn or heavy thorn. First stab the spine and the sides 3 times, 1 or 2 times, and then focus on lumbosacral region and the 5 sides, 5 times each. The diseased limbs and joints are stabbed 5 to 7 times, then the lower abdomen For local stimulus, thrashing 10 times a day is a course of treatment.

Fang 3: local lesion (Ashi acupoint).

Governing Law: Use positive puncture and heavy puncture. The degree of pain was reduced by repeatedly stabbing the plum blossom needle at the local lesion. Tap once a day.

(3) Other traditional therapies: mineral bath, foot washing, qigong, etc.

5. The above four types of syndromes commonly seen in clinical treatment of integrated traditional Chinese and western medicine. The first two types are more common in the episodes of acute arthritis and chronic arthritis, and the latter two types are more common in chronic arthritis and intermittent periods. In clinical treatment of this disease, a combination of syndrome differentiation and disease differentiation can achieve better results. It is mainly based on dialectical medicine and cooperates with modern pharmacological studies to confirm the uric acid excretion-promoting drugs, such as cork, raw oysters, Poria, Alisma, Psyllium, Dilong, Qin Zhi, Shan Ci mushroom and other drugs. The acute phase is mainly treated with colchicine and traditional Chinese medicine for clearing heat and clearing collaterals. The commonly used formula is Baihu plus Guizhi Decoction. In the chronic phase, probenecid or allopurinol should be selected according to the patient's renal function. Prescription medicine can not only reduce the amount of western medicine, but also reduce its side effects. Clinical studies have confirmed that the combined treatment of traditional Chinese medicine and western medicine is significantly more effective than those who use only western medicine and pure Chinese medicine.

6. Diet treatment is now clear. Endogenous production of uric acid in the human body accounts for 80%, and exogenous intake (produced by food decomposition) accounts for only 20%. Some scholars have conducted low-purine diet tests on gout patients, and the results can only reduce the patient's serum uric acid level by 29.7-89.2 µmol / L (0.5-1.5 mg / dl) and strictly restrict food purine for a long time, which will also limit the protein Ingestion, which affects reasonable nutrition and patients' enjoyment of diet. Due to the widespread use of anti-uric acid drugs and effective control of serum urate levels, current dietary therapy has only a supporting role.

Nonetheless, it is still meaningful to properly limit the intake of food purines: it can prevent or reduce the acute attack of gout; avoid the prolongation of the acute attack period; reduce the deposition of urate in the body and prevent the formation of uric acid stones; Thereby reducing its side effects.

(1) Maintaining ideal weight: Epidemiological investigations found that serum urate levels were positively correlated with the degree of obesity, body surface area, and body mass index. Clinical observations show that after obese patients lose weight, serum urate levels decrease, urine output decreases, and gout attacks decrease

(2) Limit food purine intake: Some scholars have suggested that the daily purine intake should be below 100-150mg, especially the intake of purine-rich foods. The purine content of commonly used foods is shown in Table 6.

Because protein has a special role in the body, too much protein intake can also increase endogenous uric acid, so it should be appropriately restricted.

(3) Encourage the selection of basic foods: foods containing more elements such as sodium, potassium, calcium, magnesium, etc., will oxidize in the body to generate alkaline oxides, such as vegetables, potatoes, sweet potatoes, milk and other physiologically called alkaline food. Fruits such as citrus, etc., are rich in potassium after being metabolized in the body, so they are also alkaline foods. Increasing the intake of alkaline foods can reduce the acidity of serum and uric acid, and even make the urine alkaline, thereby increasing the solubility of uric acid in urine. Therefore, patients should be encouraged to choose alkaline foods (Table 7). Watermelon and winter melon are not only alkaline foods, but also have obvious diuretic effects, so they are more beneficial to gout patients.

(4) Ensuring sufficient urine volume: If the patient's cardiopulmonary function is normal, the urine volume should be maintained at about 2000ml / d to promote uric acid excretion. Therefore, the total daily fluid intake of the patient should be 2500 ~ 3000ml. Drinks should be ordinary boiling water, tea, mineral water, soft drinks and fruit juice. However, drinks such as strong tea, coffee and cocoa have the effect of exciting the autonomic nervous system, which may cause gout attacks, so it should be avoided. In order to prevent nighttime urine concentration, it is more appropriate to drink water before bedtime or midnight.

Limit the total calories: The total calories are calculated according to the patient's ideal weight based on the state of rest, which usually does not exceed 105 to 126kJ (25 to 30kcal) / kg per day. Clinical experience shows that if an adult patient is moderately obese or overweight (30% to 50% overweight), total daily calories exceeding 6300kJ often cannot cause weight loss. The following methods can be used as a reference for limiting total calories and reducing weight.

A. Patients overweight 30% to 50% and above: The total calories start at 6300kJ / d and are divided into three meals for one month and then changed to 5460kJ / d; or reduce the heat energy 2310 4620kJ / d based on the original diet, The goal is to reduce body weight by 0.5 to 1.0 kg per week.

B. Overweight or mildly obese: total calories are divided into three meals starting from 6300kJ / d; or reduce the heat energy by 525 1050kJ / d based on the original diet, so as to achieve the goal of losing 0.5 to 1.0kg per month.

Distribution of three major nutrients: Under the premise of limiting total calories, the distribution principles of the three major nutrients are: high carbohydrates, medium protein and low fat.

A. Carbohydrates: Carbohydrates include vegetables and fruits and should account for 65% to 70% of total calories. This is also in line with the dietary habits of Chinese people. In this way, it can reduce the decomposition of fats to produce ketone bodies, which is beneficial to urate excretion. But you should eat as little sucrose or beet sugar as possible because they will become fructose after catabolism, but fructose can increase uric acid production. Honey also contains high fructose, so it is not suitable for consumption. Pod beans in vegetables such as tender lentils, green broad beans, and fresh peas should also be restricted due to their high purine content.

B. Protein: Protein should account for 11% to 15% of total calories, usually 0.57 to 1.Og / kg per day. Mainly use milk, cheese, skimmed milk powder and egg protein portion. Because they are high-quality proteins rich in essential amino acids, which can provide the need for continuous tissue metabolism, and contain few purines, they have almost no adverse effects on gout patients. However, yogurt contains more lactic acid and is not good for gout patients, so they are not suitable for drinking.

C. Fat: The rest of the total calories are supplemented with lipids, usually 40-50g / d. Because fat oxidizes to produce heat, it is about 2 times of carbohydrates or protein. To reduce the weight of patients, it should undoubtedly be limited. In addition, gout patients often have hypertension, arteriosclerosis, fatty liver, gallstone disease, etc., and also need a low-fat diet. Since fat prevents the normal excretion of urate, it should be restricted especially during the acute onset of gout. Animal and vegetable fat ratio should be 1: 1.5. Vegetable fat should be rich in unsaturated fatty acid vegetable oil, the choice can refer to Table 8

(5) Note:

Avoid drinking: The main component of alcohol is ethanol, which can induce glycogen dysplasia and cause lactic acid and ketones to build up in the body. -hydroxybutyric acid in lactic acid and ketone bodies can competitively inhibit uric acid excretion. Although a large amount of alcohol consumption at one time can also significantly increase serum uric acid content, induce chronic gout onset of chronic alcohol consumption, which will stimulate increased purine synthesis. High serum and urine uric acid levels. In addition, drinking beans and meat and poultry foods often will increase the intake of purine.

Limit individual purine: Limiting the intake of purine content should be treated separately according to the severity of the patient's illness, the comorbidity of the disease stage and the application of the uric acid lowering agent, that is, in line with the individual situation of the patient

Pay attention to food cooking methods: reasonable cooking methods can reduce the amount of purines contained in food, such as cooking meat first, and discarding soup before cooking. In addition, chili, curry, pepper, peppercorn mustard, ginger and other foods and seasonings can excite the autonomic nerve and induce acute gout, and should be avoided as much as possible.

Prognosis for gout and hyperuricemia

Prognosis:

The prognosis of this disease depends on the morbidity, treatment status, renal function status, and other comorbidities associated with hyperuricemia. Gout itself will not shorten life expectancy, but patients with cardiovascular disease and renal progressive disease will have a worse prognosis. Malformation and disability of joints.

prevention:

Disability analysis

(1) Acute arthritis and chronic arthritis of gout can cause multiple joints of whole body size to be affected by joint redness, swelling, heat, pain and limited movement in the acute stage. With the recurrence of acute arthritis and the enlargement of intra-articular tophi, joint structure can be destroyed, causing joint deformities and movement disorders.

(2) The incidence of renal uric acid stones in gout patients is about 25%. Stones block renal tubules, which can cause acute renal failure and endanger patients' lives.

2. Crowd prevention: Middle-aged and elderly male patients with joint pain should consider the possibility of gouty arthritis, and the serum uric acid content can be measured for screening.

3. Individual prevention

(1) Primary prevention: diet control: patients with gout should use a low-calorie diet to maintain the ideal weight. At the same time, avoid high-purine foods, which mainly include animal viscera sardines, clams, snakes and other seafood and thick broth, followed by fish and shrimp, meat, peas, etc. A variety of cereal products, fruits, vegetables, milk, dairy products, eggs, tofu and soy milk, containing the least purine. Strictly abstain from drinking alcohol and drink plenty of water to maintain urine output

(2) Secondary prevention: Avoid the inducement of urate crystallization: Avoid cold and dampness, excessive fatigue, mental stress, wear shoes comfortably, prevent joint damage, and use drugs that affect uric acid excretion, such as diuretics, low-dose aspirin Wait. Middle-aged and elderly men with a family history of classic arthritic symptoms should consider this disease in order to achieve early diagnosis.

(3) Tertiary prevention: If there is a danger of puncture of huge gout stones, or if it affects joint function near the joint, surgical resection should be considered. For those who have penetrated to form the sinus, the urate crystals can be scraped off. After the granulation tissue is formed, the skin grafts, such as the joints, have been severely damaged. If necessary, joint fusion can be performed.

Prevention and treatment of concomitant diseases: simultaneous treatment of concomitant hypertension, hyperlipidemia, diabetes, coronary heart disease, cerebrovascular disease, etc.