Pathophysiology
Summary
Gout is a type of inflammatory arthritis initiated when excess uric acid crystallizes into monosodium urate crystals in joint tissue. Gout only develops after at least 10 yrs of sustained hyperuricemia. The source of this excessive uric acid is the degradation of purine nucleotides (AMP & GMP) into xanthine, which is subsequently converted to uric acid by xanthine oxidase. Gout frequently afflicts middle-aged & post-menopausal people, especially those with conditions like metabolic syndrome, hypertension, and type 2 diabetes.
The strongest risk factor for gout is chronic hyperuricemia, which can occur due to underexcretion or overproduction of uric acid. Uric acid underexcretion is the most prevalent form, and is commonly idiopathic; however, it can arise in chronic kidney disease (CKD) due to impaired uric acid excretion and from medications like thiazides & loop diuretics that increase reabsorption.
Overproduction of uric acid can result from conditions that increase cell turnover, such as in hemolytic diseases or chemotherapy, where an influx of purine released from cell lysis causes hyperuricemia. Overproduction also occurs in Lesch-Nyhan syndrome, which results from mutations in the HGPRT enzyme of the purine salvage pathway, resulting in hyperuricemia and a predisposition to gout, as well as other conditions like renal dysfunction, intellectual disability, and self-mutilation.
Acute gout episode are precipitated by sudden changes in serum uric acid levels, which can be induced by medications like aspirin, syndromes like the tumor lysis syndrome, or intake of purine-rich foods and drinks, including meat and alcohol. A typical gout attack presents with abrupt joint pain, mainly in the MTP (great toe) or knee. The underlying pathophysiology involves monosodium urate crystals triggering an inflammatory response marked by redness, swelling, and joint tenderness. Synovial fluid examination during an acute gout flare will reveal negatively birefringent needles, appearing yellow when parallel to polarizing light, and an increased WBC count.
Chronic neglect of gout leads to chronic gout, characterized by recurrent attacks that involves multiple joints. Persistent hyperuricemia can also result in urate kidney stones, and in extreme cases, a sudden spike in uric acid can precipitate acute urate nephropathy, manifesting as acute kidney injury.
In contrast, calcium pyrophosphate dihydrate crystal deposition (CPPD) disease or ‘pseudogout’ is cause by calcium pyrophosphate dihydrate crystals amassing in joint cartilage. This condition primarily affects individuals older than 65, especially those with osteoarthritis. The risk factors are summarized by the mnemonic 4 H's: Hemochromatosis, Hyperparathyroidism, Hypomagnesemia, and Hypophosphatasia. Acute CPP crystal arthritis symptoms mirror those of gout with painful, swollen, and warm joints, commonly affecting the knee. Joint aspiration is used to discern the two, with CPPD revealing rhomboid crystals in synovial fluid. These CPP crystals are positively birefringent, appearing blue when viewed parallel to polarized light. Chronic CPPD disease is radiologically evident as chondrocalcinosis on x-ray, signifying calcium deposits within joint cartilage.
Lesson Outline
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FAQs
When uric acid accumulates in tissues, it precipitates into monosodium urate crystals, leading to joint inflammation. Maintaining uric acid levels below the saturation point of 6.8mg/dL is crucial to prevent gout, which can only develop after 10 years of hyperuricemia. Additionally, managing associated risk factors such as metabolic syndrome, hypertension, and type 2 diabetes, especially in middle-aged or post-menopausal individuals, can further reduce the risk of developing gout.
Purine nucleotides like AMP and GMP are metabolized to xanthine, which is subsequently converted to uric acid by the enzyme xanthine oxidase. If the production of uric acid exceeds the body's ability to excrete it, hyperuricemia ensues, setting the stage for gout development.
Acute gout flares are often precipitated by sudden shifts in serum uric acid levels. Common culprits include purine-rich foods such as meat and alcohol, medications like aspirin and certain diuretics, as well as in conditions that increase cell turnover. Avoiding these triggers, coupled with a balanced diet and consistent exercise, can help in managing and preventing acute gout episodes.
Acute gout typically manifests as abrupt joint pain, frequently affecting the MTP of the great toe or the knee, accompanied by inflammation-induced redness, swelling, and tenderness. Chronic neglect of gout leads to chronic gout, characterized by recurrent attacks that can involves multiple joints.
CPPD disease arises from the accumulation of calcium pyrophosphate dihydrate crystals in joint cartilage. Unlike gout, it predominantly affects individuals over 65 years and targets the knee or other extremity joints. Diagnostic differentiation involves joint aspiration, revealing rhomboid crystals and neutrophils in the synovial fluid. These CPP crystals are positively birefringent, appearing blue under parallel polarized light. Chronic CPPD will also display chondrocalcinosis on x-ray, a feature not seen in gout.
