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Clinical Category Metabolic Defect

Primary Gout (90% of cases)

Enzyme defects unknown (85%–90% of primary gout) n Overproduction of uric acid

••Normal excretion (majority)

••Increased excretion (minority)

••Underexcretion of uric acid with normal production

Known enzyme defects—e.g., partial HGPRT deficiency (rare) n Overproduction of uric acid

Secondary Gout (10% of cases)

Associated with increased nucleic acid turnover—e.g., leukemias n Overproduction of uric acid with increased urinary excretion

Chronic renal disease n Reduced excretion of uric acid with normal production

Inborn errors of metabolism—e.g., complete HGPRT deficiency (Lesch-Nyhan

syndrome)

n Overproduction of uric acid with increased urinary excretion

HGPRT, hypoxanthine guanine phosphoribosyl transferase.

and in some cases gouty arthritis. Less severe deficiencies of the enzyme may also induce hyperuricemia and gouty arthritis with only mild neurologic deficits, but together these causes

of gout are uncommon. The great majority of cases of gout are primary, in which the metabolic defect underlying the increased levels of uric acid is unknown.

As stated earlier, hyperuricemia does not necessarily lead to gouty arthritis. Many factors contribute to the conversion of asymptomatic hyperuricemia into primary gout, including the

following:

Age of the individual and duration of the hyperuricemia are factors. Gout rarely appears before 20 to 30 years of hyperuricemia.

Genetic predisposition is another factor. In addition to the well-defined X-linked abnormalities of HGPRT, primary gout follows multifactorial inheritance and runs in families.

• Heavy alcohol consumption predisposes to attacks of gouty arthritis.

Obesity increases the risk of asymptomatic gout.

• Certain drugs (e.g., thiazides) predispose to the development of gout.

Lead toxicity increases the tendency to develop saturnine gout ( Chapter 9 ).

Central to the pathogenesis of the arthritis is precipitation of monosodium urate crystals into the joints ( Fig. 26-47 ). Synovial fluid is a poorer solvent for monosodium urate than

plasma, and so with hyperuricemia the urates in the joint fluid become supersaturated, particularly in the peripheral joints (ankle), which may have temperatures as low as 20°C. With

prolonged hyperuricemia, crystals and microtophi of urates develop in the synovium and in the joint cartilage. Some unknown event, possibly trauma, then initiates release of crystals

into the synovial fluid, which begins a cascade of events. The released crystals are chemotactic to leukocytes and also activate complement,

Figure 26-46Purine metabolism. The conversion of PRPP to purine nucleotides is catalyzed by amido PRT in the de novo pathway and by APRT and HGPRT in the salvage pathway.

APRT, amido-phosphoribosyltransferase; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; PRPP, phosphoribosyl pyrophosphate; PRT, phosphoribosyltransferase.

Figure 26-47Pathogenesis of acute gouty arthritis.



Figure 26-48Amputated great toe with white tophi involving the joint and soft tissues.

Figure 26-49Photomicrograph of a gouty tophus. An aggregate of dissolved urate crystals is surrounded by reactive fibroblasts, mononuclear inflammatory cells, and giant cells.

Figure 26-50Smear preparation of synovial fluid containing calcium pyrophosphate crystals.

Figure 26-51Excised synovium with fronds and nodules typical of pigmented villonodular synovitis (PVNS) (arrow).

Figure 26-52Sheets of proliferating cells in PVNS bulging the synovial lining.

TABLE 26-8-- Soft Tissue Tumors

n Tumors of adipose tissue

••Lipomas

••Liposarcoma

n Tumors and tumor-like lesions of fibrous tissue

••Nodular fasciitis

••Fibromatoses

••••Superficial fibromatoses

••••Deep fibromatoses

••Fibrosarcoma

n Fibrohistiocytic tumors

••Fibrous histiocytoma

••Dermatofibrosarcoma protuberans

••Malignant fibrous histiocytoma

n Tumors of skeletal muscle

••Rhabdomyoma

••Rhabdomyosarcoma

n Tumors of smooth muscle

••Leiomyoma

••Smooth muscle tumors of uncertain malignant potential

••Leiomyosarcoma

n Vascular tumors

••Hemangioma

••Lymphangioma

••Hemangioendothelioma

••Hemangiopericytoma

••Angiosarcoma

n Peripheral nerve tumors

••Neurofibroma

••Schwannoma

••Granular cell tumor

••Malignant peripheral nerve sheath tumors

n Tumors of uncertain histogenesis

••Synovial sarcoma

••Alveolar soft part sarcoma

••Epithelioid sarcoma

at least 100:1. In the United States, little more than 8000 sarcomas are diagnosed annually (0.8% of invasive malignancies), yet they are responsible for 2% of all cancer deaths,

reflecting their lethal nature.


Date: 2016-04-22; view: 800


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