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Crystal Deposition Diseases
The three most common crystal-induced arthropathies are caused by precipitation of monosodium urate monohydrate, calcium pyrophosphate dihydrate, and basic calcium phosphate and are termed gout, calcium pyrophosphate arthropathy , and basic calcium arthropathy , respectively. Basic calcium crystals are ultramicroscopic in size and are not detected by the compensated polarized microscopy used to identify monosodium urate and calcium pyrophosphate dehydrate crystals. Like monosodium urate and calcium pyrophosphate crystals, basic calcium phosphate crystals are biologically active and can accelerate atrophic changes in bone and cartilage.
Gout and Hyperuricemia
Definition
Gout is a metabolic disorder that results from the tissue deposition of monosodium urate crystals in or around joints and/or the crystallization of uric acid in the renal collecting system. Gout is the most common inflammatory joint disease in men and in older women. The metabolic derangement responsible for gout is the supersaturation of blood and body fluids with the urate ion to the point that crystal formation is possible. At physiologic pH and at normal body temperature, urate is considered to be supersaturated at concentrations of 6.8 mg/dL or greater. Therefore, from a biologic perspective, hyperuricemia is any serum urate level greater than 6.8 mg/dL in both men and women. Although hyperuricemia is a necessary prerequisite for developing gout, only 20% of all hyperuricemic subjects will ultimately develop gout.
Epidemiology
The incidence and prevalence of gout vary greatly throughout the world. In the United States, the United Kingdom, and much of Western Europe, the prevalence of gout ranges from 3 to 6% in men and 1 to 2% in women. In developing countries the prevalence is much lower, typically less than 1%. However, the highest prevalences have been noted in certain ethnic groups, especially in Oceanic populations, including Taiwanese Aborigines, Māori, and Pacific Islanders living in New Zealand, where prevalence estimates are more than 10%. , In Western societies, including the United States, the rate has more than doubled within the past three decades. Factors that have been proposed to explain this dramatic rise include the overall increase in longevity; the increased prevalence of hypertension, metabolic syndrome, and obesity; the increased use of thiazide diuretics and low-dose aspirin; changes in dietary trends, including the greater use of high-fructose corn syrup as a sweetener; and finally, the increase in survival of patients with end-stage renal disease and after organ transplantation.
The degree of elevation of the serum urate is directly correlated with the likelihood of developing gout. The reported annual incidence of gout in individuals with baseline serum urate levels of 9 mg/dL or higher is 4.9%, compared with only 0.5% in people with serum urate levels of 7.0 to 8.9 mg/dL.
Pathobiology
Uric acid is the end product of purine metabolism in humans. Urate is produced by the conversion of a very soluble molecule, hypoxanthine, to the less soluble xanthine, which, in turn, is converted to the very insoluble uric acid by progressive purine ring oxidations catalyzed by the enzyme xanthine oxidase. Xanthine oxidase is present in several organs, but most activity in the body is found in the liver and intestines. In most mammals, purine catabolism is taken one step further through the enzyme uric acid oxidase or uricase, with the purine end product in these species being the very soluble allantoin. Humans and most other hominoids lost the ability to produce the enzyme uricase nearly 18 million years ago. As a result, uric acid accumulation is possible. Whether caused by overproduction of uric acid or its underexcretion by the kidneys, this accumulation leads to supersaturation of urate ion in blood and the precipitation of monosodium urate crystals in synovial fluid, soft tissues, and organs.
Because of urate’s potential for causing disease, its elimination is very important. The total daily accumulation of uric acid from de novo synthesis, nucleotide degradation, and dietary consumption is normally balanced by renal excretion of approximately two thirds of the total urate turnover and by intestinal elimination of the remaining one third.
Hyperuricemia occurs when urate production is not balanced by renal excretion. In more than 90% of all patients with gout, the cause of this imbalance is renal underexcretion. Fewer than 10% of cases of gout are caused by the overproduction of purine or by a combination of overproduction and underexcretion. The nongenetic causes of hyperuricemia include other medical conditions, dietary components, and medications ( Table 252-1 ). These factors may result in either overproduction or diminished renal clearance of uric acid. Similarly, the genetic causes of hyperuricemia ( Table 252-2 ) may affect either production or elimination of uric acid.
TABLE 252-1
NONGENETIC CAUSES OF HYPERURICEMIA
| IMPAIRED URIC ACID EXCRETION |
| Clinical Conditions |
| Reduced glomerular filtration rate Hypertension Obesity Lead nephropathy |
| Drugs |
| Thiazide diuretics Ethanol Low-dose salicylates (0.06-3.0 g/day) Cyclosporine Tacrolimus Levodopa Angiotensin-converting-enzyme inhibitors β-Blockers Nicotinic acid Pancreatic extract |
| EXCESSIVE URIC ACID PRODUCTION |
| Clinical Conditions |
| Myeloproliferative and lymphoproliferative neoplasms Obesity Psoriasis |
| Diet Components |
| Alcoholic beverages (especially beer) Red meat, organ meat, shellfish High fructose corn syrup |
TABLE 252-2
GENETIC CAUSES OF HYPERURICEMIA
| SYNDROME | PHENOTYPE |
|---|---|
| INBORN ERRORS OF PURINE METABOLISM | |
| Hypoxanthine-guanine phosphoribosyl transferase deficiency Phosphoribosyl pyrophosphatase synthetase overactivity |
Neurologic dysfunction, renal stones, early-onset gout Neurologic dysfunction, early-onset gout |
| EXCESSIVE CELL DEATH AND URATE GENERATION | |
| Glycogen storage disease I
Glycogen storage disease III Myoadenylate deaminase deficiency |
Growth restriction, lactic acidosis, early-onset gout Early-onset gout Early-onset gout Early-onset gout Growth restriction, liver failure, early-onset gout Myopathy, gout Rhabdomyolysis, gout |
| REDUCED RENAL EXCRETION OF URIC ACID | |
| Medullary cystic kidney disease
Familial juvenile hyperuricemic nephropathy
|
Renal dysfunction, early-onset gout Renal dysfunction, early-onset gout Familial gout |
Renal Urate Underexcretion
Because uric acid is small and not protein bound, it is completely filtered by the glomerulus. In normal persons, approximately 8 to 10% of the filtered load is ultimately cleared in the urine. The various renal tubular transporters that are responsible for determining how much of the filtered uric acid is actually excreted are located in the proximal convoluted tubules and are referred to collectively as the transportasome ( E-Fig. 252-1 ). Both reabsorption and secretion occur in this segment through the actions of several organic acid transporters, with the net effect being the reabsorption of nearly 90% of the uric acid filtered at the glomerulus. These organic acid transporters are also responsible for eliminating organic acids other than uric acid as well as many commonly used medications. The most important tubular transporter of uric acid is URAT1 . This transporter swaps urate ions for other monocarboxylate organic ions in both directions across the luminal membrane of proximal tubular cells. This system can be driven to reabsorb more uric acid from the tubular lumen by raising tubular epithelial concentrations of lactate, pyruvate, or the ketoacids acetoacetate and β-hydroxybutyrate. Certain drugs, when present in the tubular lumen, can displace uric acid from the transporter, thereby causing more uric acid to be lost in the urine. These uricosuric agents include probenecid.
When the renal clearance of uric acid is compared between normal adult men and gouty men, the gouty subjects excrete only 70% as much uric acid as normal individuals at any given serum urate concentration. In general, gouty patients require a serum urate concentration to be 1.7 mg/dL higher to obtain the same level of excretion as seen in normal individuals.
Most genetic polymorphisms associated with gout in genome-wide association studies encode for the various components of the uric acid transportasome (see E-Fig. 252-1 ). Polymorphisms in the glucose transporter GLUT-9 (encoded by the SLC2A9 gene) are statistically the most significant determinants of serum urate. ABCG2 is a multifunctional transporter that belongs to the adenosine triphosphate (ATP)-binding cassette family found primarily in the small intestine and liver. Polymorphisms in the gene encoding URAT1 may lead to either hypouricemia or hyperuricemia. A loss-of-function mutation results in familial renal hypouricemia.
The serum urate variance explained by these common genetic variants is only about 6% of the total variance observed between gouty and non-gouty individuals. Similar risk-stratifying techniques demonstrate that 67% of the variance is caused by nongenetic factors such as the serum creatinine level, the consumption of ethanol, and the components of the metabolic syndrome.
Urate Overproduction
Traditionally, the causes of hyperuricemia were attributed to either the overproduction of urate or its underexcretion in the urine. The former was presumed to be the case when hyperuricemia occurred despite a 24-hour urinary uric acid collection showing more than 1000 mg while eating a standard Western diet. In many of these cases, the hyperuricemia reflects accelerated cell turnover (e.g., lymphoproliferative and myeloproliferative diseases, psoriasis, chronic hemolytic states, polycythemia vera, and certain muscle glycogenoses) or by enhanced breakdown of purine nucleotides (e.g., alcohol use disorder or ingestion of fructose). In addition to these secondary causes of urate overproduction, primary inborn errors of metabolism (e.g., phosphoribosyl pyrophosphate [PRPP] synthetase overactivity) can result in increased de novo purine synthesis, or decreased purine salvage (e.g., complete and partial hypoxanthine-guanine phosphoribosyltransferase [HPRT] deficiencies [Lesch-Nyhan syndrome and Kelley-Seegmiller syndrome, respectively]). Polymorphisms in the ABCG2 urate transporter gene in the bowel can lead to extrarenal underexcretion of uric acid. This mechanism may account for a large percentage of cases previously considered to be due to overproduction of urate.
Pathogenesis of Monosodium Urate Monohydrate Crystals and Inflammation
Monosodium urate crystals in joints, soft tissues, and organs are the cause of pain and destruction in gout. Urate crystals will form only when physiologic conditions permit. In plasma, urate becomes insoluble at concentrations of 6.8 mg/dL (408 µmol/L) with a pH of 7.40 and normal body temperature. A reduction in pH or temperature will lower the solubility threshold even further. Not all people who are hyperuricemic will form crystals, however, and genetic factors other than those responsible for hyperuricemia affect when crystallization will occur.
Monosodium urate crystals form in joints and soft tissues of individuals long before they cause any symptoms of gout. Crystals deposit in small lattice structures called microtophi on the surface of cartilage and synovial lining. These microtophi slowly grow but are generally stable as long as the environment surrounding them does not change drastically with regard to pH, urate concentration, or temperature. At the time of the first and subsequent flares, these crystal lattice structures break apart and shed a massive number of crystals into the joint space. These newly released and nonopsonized crystals, which are not coated with albumin or immunoglobulins, activate receptors on synovial macrophages and are then phagocytized by monocytes and macrophages, thereby leading to the cytoplasmic assembly and activation of the NLRP3 inflammasome. The resulting rapid production of interleukin-1β is responsible for gout’s cardinal features of severe inflammation.
Although monocytes and macrophages are the major cellular sources of IL-1β, neutrophils predominate at the site of inflammation (e.g., joint), where monosodium urate crystals become extremely pro-inflammatory by recruiting neutrophils that then generate reactive oxygen species. However, neutrophils also have a major role in the resolution of acute gout through the formation of neutrophil extracellular traps (NETs). Neutrophil proteases are released into the NETs and cause the formation of cell aggregates that contain cellular debris and DNA. These cellular aggregates within NETs can rapidly degrade pro-inflammatory cytokines, thereby allowing for the spontaneous resolution of joint inflammation after 3 to 6 days, even in the absence of treatment.
Clinical Manifestations
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