Gout is a metabolic disorder of purine metabolism characterized by recurrent episodes of acute arthritis associated with the presence of monosodium urate monohydrate crystals in the synovial fluid leukocytes and, in many cases, gross deposits of sodium urate (tophi) in periarticular soft tissues. Tophi, a pathognomonic feature of gout, typically form on pressure points in and around the inflamed joints. Serum uric acid concentrations are elevated; however, hyperuricemia does not necessarily lead to gout, and patients with gout may occasionally present with normal serum uric acid levels. Crystal deposits cause acute inflammation of the articular and paraarticular soft tissues, whereas recurrent acute intermittent flares can result in chronic gouty arthritis leading to cartilage and bone destruction.

Gouty arthritis accounts for ˜5% of all arthritides. Four stages of the disease have been recognized: asymptomatic hyperuricemia, acute gouty arthritis, intercritical gout, and chronic tophaceous gout. Articular manifestations occur in the different stages of the disease. Ninety percent of the first gout attacks are monoarticular. The great toe is the most common site of involvement in gouty arthritis; the condition known as podagra, which involves the first metatarsophalangeal joint, occurs in ˜75% of patients. Other frequently affected sites include the ankles, knees, hands, wrists, and elbows. Most patients are men, showing the higher prevalence after the age of 65 years, but gouty arthritis is seen in postmenopausal women as well (men-to-women ratio being 20:1). Recent data from genome-wide association studies (GWAS) show that genetic variants of SLC2A9/GLUT9 were associated with lower serum uric acid levels, and the values were higher among women, and, conversely, genetic variants of protein ABCG2 were associated with higher serum uric acid levels, and the values were higher among men. These studies point to GLUT9 and ABCG2 as being important modulators of uric acid levels and playing important role in the risk of gout.

Uric acid is the end product of catabolism of purine, a component of nucleic acid (DNA and RNA), and because humans lack the enzyme uricase, increased synthesis of uric acid or decreased secretion of uric acid by the kidneys leads to hyperuricemia. In another way, an increased miscible pool of uric acid with resulting hyperuricemia can occur only in two principal ways: first, urate is produced in such large quantities that, even though excretion routes are of normal capacity, they are inadequate to handle the excessive load; second, the capacity for uric acid excretion is critically reduced so that even a normal quantity of uric acid cannot be eliminated.

In 25% to 30% of gouty patients, a primary defect in the rate of purine synthesis causes excessive uric acid
formation, as reflected in excessive urinary uric acid excretion (more than 600 mg/day) measured while the patient is maintained on a standard purine-free diet. Increased production can also be seen in gout secondary to myeloproliferative disorders associated with increased destruction of cells and result in increased breakdown of nucleic acids. Decreased excretion occurs in primary gout in patients with a dysfunction in the renal tubular capacity to excrete urate and in patients with chronic renal disease. In most patients, however, there is evidence of both: uric acid overproduction and diminished renal excretion of uric acid.

The chance of development of gouty arthritis in hyperuricemic individuals should increase in proportion to the duration and, even more, to the degree of hyperuricemia. Monosodium urate, however, has a marked tendency to form relatively stable supersaturated solutions; therefore, the proportion of hyperuricemic patients in whom gouty arthritis actually develops is relatively low. The clinical development of gouty arthritis in the hyperuricemic subject is also substantially influenced by other factors, such as binding of urate to plasma proteins or the presence of promoters or inhibitors of crystallization.

A wet preparation of fresh synovial fluid is best for the examination of crystals. Although crystals may often be seen by ordinary light microscopy, reliable identification requires polarization equipment. The identification of the crystals by polarized light microscopy requires a polarizing microscope with a compensating first-order red filter. With the red filter in position, the crystals in the synovial fluid should be aligned so that their long axis is parallel to the line that is drawn on the compensating filter, which is the axis of slow vibration. This allows differentiating between urate and pyrophosphate crystals—characteristics of gout and CPPD, respectively. Because both types of crystals are birefringent, they refract the polarized light that passes through them. The birefringence phenomenon is caused by the refractive index for light, which vibrates either parallel or perpendicular to the axis of the crystal being viewed. Color is the key to negative or positive birefringence. Sodium urate crystals are usually needle shaped and exhibit strong negative birefringence, and they appear bright yellow when the longitudinal axis of the crystal is parallel to the axis of slow vibrations of the red compensator of the polarizing system, but they appear blue when perpendicular (see Figs. 1.11 and 1.12). Conversely, calcium pyrophosphate dihydrate crystals are usually rhomboidal and exhibit weakly positive birefringence, appearing blue and less bright than urate crystals when their long axis is aligned with the line on the compensating filter (see Fig. 1.10).

Monosodium urate crystals, the pathogens of gouty arthritis, range in length from 2 µm to 10 µm and are found within synovial leukocytes or extracellularly in virtually every case of acute gout, although the likelihood of finding such crystals varies inversely with the amount of time elapsed from the onset of symptoms to the time of examination. Crystals from tophi may be larger.

Prolonged hyperuricemia leads to the accumulation of monosodium urate crystals in the joints and soft tissues, which usually results in the formation of nodular masses known as tophi. The accumulation of the crystals within bone marrow and articular cartilage induces a chronic inflammatory reaction with consequent bone resorption and erosions (Fig. 7.1). The chalky tophi consist of large deposits of crystal surrounded by highly vascularized inflammatory tissue rich in mononuclear histiocytes, fibroblasts, and giant cells (Fig. 7.2). The synovium of a joint affected by acute gout shows villous hyperplasia and synoviocyte hypertrophy and hyperplasia. The subintima and synoviocyte layer are heavily infiltrated by large number of polymorphonuclear leukocytes and fewer macrophages and lymphocytes.

Gouty arthritis has several characteristic imaging features. Erosions, which are usually sharply marginated, are initially periarticular in location (Fig. 7.3) and are later seen to extend into the joint (Fig. 7.4); an “overhanging edge” of erosion is a frequent identifying feature (Figs. 7.5, 7.6, 7.7). Occasionally, intraosseous defects are present secondary to the formation of intraosseous tophi (Figs. 7.8 and 7.9). Usually, there is a striking lack of osteoporosis, which



helps differentiate this condition from rheumatoid arthritis. The reason for the absence of osteoporosis is that the duration of an acute gouty attack is too short to allow the development of the disuse osteoporosis so often seen in patients with rheumatoid arthritis. If erosion involves the articular end of the bone and extends into the joint, part of the joint is usually preserved (Fig. 7.10A, see also Fig. 7.5). Unlike rheumatoid arthritis, periarticular and articular erosions are asymmetric in distribution (Fig. 7.11). In chronic tophaceous gout, monosodium urate crystal deposit in and around the joint is seen, creating dense masses in the soft tissues called tophi, which frequently exhibit calcifications (Figs. 7.12, 7.13, 7.14, 7.15, see also Figs. 7.1 and 7.2). Characteristically, tophi are randomly distributed



and are usually asymmetric; if they occur in the hands or feet, they are more often seen on the dorsal aspect (Fig. 7.16). Currently, dual-energy CT (DECT) color-coded images can accurately depict gouty tophi (Figs. 7.17, 7.18, 7.19, 7.20, see also Figs. 2.27 and 2.28). DECT has ability to extract information and characterize the chemical composition of material according to the differential x-ray photon energy-dependent attenuation of compounds being examined at two different energy levels. Reported sensitivity of this technique varies between 78% and 100% and specificity between 89% and 100%. Magnetic resonance imaging is also an effective way to detect articular and soft tissue abnormalities of gouty arthritis. Tophaceous gouty deposits exhibit a wide spectrum of signal intensities characteristics, which reflects their variable composition and relative proportion of protein, fibrous tissue, crystals,


and hemosiderin. Most lesions are isointense relative to muscle on T1-weighted images, and low-to-intermediate heterogeneous signal intensity on proton density-weighted and water-sensitive (IR, T2) sequences (Fig. 7.21). There is strong enhancement following intravenous injection of gadolinium, although contrast enhancement of the tophus is variable and depends on the vascularity of the affected synovium and surrounding granulation tissue (Fig. 7.22). Concomitant enhancement of adjacent tendon sheaths, ligaments, muscles, and bone marrow may also be present, reflecting intense inflammatory reaction.

Although imaging findings of gouty arthritis are generally very characteristic and most of the time even pathognomonic, clinical presentation of acute gouty arthritis may be sometimes mistaken for septic arthritis. The two conditions may present with similar symptoms including joint pain, swelling, tenderness, and occasionally similar laboratory findings such as elevated white blood cell count and sedimentation rate. Soft tissue tophi may at times mimic rheumatoid nodules. Intraosseous tophi may have aggressive appearance and thus may simulate malignant bone tumor. On radiography, articular gouty erosions, particularly affecting the proximal and distal interphalangeal joints, may sometimes mimic erosive osteoarthritis. Amyloid infiltrate of the articular structures may cause soft tissue masses accompanied by cystic and erosive lesions indistinguishable from those of gout. Finally, it has to be pointed out that gout may coexist with other arthropathic conditions such as rheumatoid arthritis, osteoarthritis, and infectious arthritis.

CPPD crystal deposition disease is a metabolic disorder, which is characterized by the accumulation of calcium pyrophosphate dihydrate crystals in intra-articular and periarticular tissues, most commonly within fibrocartilage and hyaline cartilage. In addition, synovial, bursal, ligamentous, and tendinous calcifications are encountered. It rarely presents as a soft tissue mass in extra-articular location, which is known as tumoral or tophaceous pseudogout. The condition may occur as a hereditary or sporadic disorder. Some investigators suggested that a putative pyrophosphate transporter, the progressive ankylosis protein homolog, a protein encoded by ANKH gene, might be responsible for this disease. ANKH may also play a role in modulating the enzymes involved in mineralization, such as alkaline phosphatase, thus potentially contributing to the disease process. The men and women are equally affected; most commonly, patients are middle aged and older. The disease may be asymptomatic, in which case the only imaging finding may be chondrocalcinosis (see text below). When symptomatic, it is called pseudogout. There is, however, a great deal of confusion about these terms, and they are often misused.

In an effort to explain the relationship between chondrocalcinosis, calcium pyrophosphate arthropathy, and the pseudogout syndrome, Resnick has proposed an integration of these terms under the rubric CPPD crystal deposition disease. Chondrocalcinosis, a condition in which calcification of the hyaline (articular) cartilage or fibrocartilage (menisci) occurs, may be seen in other disorders as well, such as gout, hyperparathyroidism, hemochromatosis, hepatolenticular degeneration (Wilson disease), and degenerative joint disease (Table 7.2). Calcium pyrophosphate arthropathy refers to CPPD crystal deposition disease affecting the joints and producing structural damage to the articular cartilage. It displays distinctive imaging abnormalities such as narrowing of the joint space, subchondral sclerosis, and osteophytosis, similar to osteoarthritis. The pseudogout syndrome represents a condition in which symptoms such as acute pain are similar to those seen in gouty arthritis; however, it does not respond to the usual treatment (colchicine) for the latter disease.

Calcium pyrophosphate crystals, the pathogens in pseudogout, range up to 10 µm in length. As in gout, many intracellular crystals are seen during an acute episode. The colors are usually but not always much less intense than urates, that is, they are weakly birefringent. Pyrophosphate crystals are generally chunkier and often show a line down the middle. The most common form of calcium pyrophosphate crystal is a rhomboid. Pyrophosphate crystals are positively birefringent in that they are blue when the longitudinal axis of the crystal is parallel to the slow vibrations axis of the red compensator and yellow when it is perpendicular (see previous text and Figs. 1.9 and 1.10). Pathologic findings consist of punctate or linear calcium deposits, usually in the hyaline cartilage paralleling the subchondral bone end plate, also referred to as a “subchondral” or “articular” cortex (Fig. 7.23). Punctate calcifications may also be seen in synovial tissue (Fig. 7.24). On microscopic examination, the chalky white deposits appear either crystalline or amorphous. In the vascularized tissue, there is associated inflammatory infiltrate that includes monophages and phagocytic polykaryons. In nonvascularized tissue, no inflammatory reaction is present. The pyrophosphate crystals are distinguished from urate crystals by their rhomboid shape (Fig. 7.25) and by their weakly positive birefringence (see prior text).