Thesis Abstract

Abstract
Gout is a common form of inflammatory arthritis caused by the deposition of monosodium urate crystals in joints and tissues due to elevated levels of uric acid in the blood, a condition known as hyperuricemia. This review focuses on the biochemistry of gout, exploring the underlying mechanisms of urate crystal formation, inflammation, and tissue damage in the context of this disease. The primary risk factor for gout is hyperuricemia, which results from an imbalance between the production and excretion of uric acid. Uric acid is a byproduct of purine metabolism and is normally excreted by the kidneys. Various genetic and environmental factors can disrupt this balance, leading to the accumulation of uric acid in the blood and eventual crystal deposition in the joints. The formation of monosodium urate crystals, the hallmark of gout, triggers an inflammatory response mediated by the innate immune system. Urate crystals are recognized by immune cells, particularly macrophages, which activate the NLRP3 inflammasome and release pro-inflammatory cytokines such as interleukin-1? (IL-1?). This cascade of events results in the recruitment of neutrophils and other immune cells to the site of crystal deposition, causing pain, swelling, and tissue damage. Chronic gout is characterized by the presence of tophi, which are collections of urate crystals surrounded by inflammatory cells and fibrous tissue. Tophi can develop in the joints, tendons, and other tissues, leading to chronic inflammation and joint damage. In addition to the joint manifestations of gout, the disease is associated with systemic inflammation and an increased risk of cardiovascular comorbidities. Current treatments for gout focus on reducing symptoms, lowering serum uric acid levels, and preventing flares. Lifestyle modifications such as dietary changes and weight loss can help reduce the risk of gout attacks. Pharmacological agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, corticosteroids, and urate-lowering drugs are commonly used to manage acute flares and prevent long-term complications. In conclusion, gout is a complex metabolic disorder with a strong inflammatory component. Understanding the biochemistry of gout is essential for developing targeted therapies that can effectively control symptoms, prevent complications, and improve the quality of life for patients with this debilitating disease.

Thesis Overview

1.1     Introduction

Gout was described by Hippocrates as “the disease of kings” due to its association with rich diet. (Falasca, 2006). Gout is a heterogeneous group of diseases resulting from the deposition of urate (as monosodium urate monohydrate) crystals in supersaturated extracellular fluids. It’s also a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot, and swollen joint (Chen and Schumacher, 2008). Pain typically comes on rapidly in less than twelve hours (Richette and Bardin, 2010). The joint at the base of the big toe is affected in about half of cases (Schlesinger, 2010). It may also result in tophi, kidney stones, or urate nephropathy (Richette and Bardin, 2010).

Gout is due to persistently elevated levels of uric acid in the blood. This occurs due to a combination of diet and genetic factors (Richette and Bardin, 2010). At high levels, uric acid crystallizes and the crystals deposit in joints, tendons, and surrounding tissues, resulting in an attack of gout which may be first acute an then to chronic gouty arthritis. Nodular masses of monosodium urate crystals may be deposited in the soft tissues, resulting in chronic tophaceous gout. Gout occurs more commonly in those who regularly eat meat or seafood, drink beer, or are overweight (Beyl et al., 2016). Diagnosis of gout may be confirmed by the presence of crystals in the joint fluid or tophus. Blood uric acid levels may be normal during an attack (Richette and Bardin, 2010).

Gout affects about 1 to 2% of the Western population at some point in their lives. It has become more common in recent decades (Richette and Bardin, 2010). This is believed to be due to increasing risk factors in the population, such as metabolic syndrome, longer life expectancy, and changes in diet (Richette and Bardin, 2010). Older males are most commonly affected.

1.2     Signs and symptoms

          Gout can present in multiple ways, although the most usual is a recurrent attack of acute inflammatory arthritis (a red, tender, hot, swollen joint) (Chen and Schumacher, 2008). The metatarsal-phalangeal joint at the base of the big toe is affected most often, accounting for half of cases (Schlesinger, 2010). Other joints, such as the heels, knees, wrists, and fingers, may also be affected (Schlesinger, 2010). Joint pain usually begins over 2–4 hours and during the night (Schlesinger, 2010). This is mainly due to lower body temperature (Eggebeen, 2007). Other symptoms which may rarely occur along with the joint pain include fatigue and a high fever (Eggebeen, 2007).

          Long-standing elevated uric acid levels (hyperuricemia) may result in other symptoms, including hard, painless deposits of uric acid crystals known as tophi. Extensive tophi may lead to chronic arthritis due to bone erosion (Terkeltaub, 2010). Elevated levels of uric acid may also lead to crystals precipitating in the kidneys, resulting in stone formation and subsequent urate nephropathy (Tausche et al., 2009)