Gout as a Metabolic Disorder - Research Paper Example

? GOUT Word Count 2766 INTRODUCTION Gout is a metabolic disorder ically represented as acute inflammatory monarthritis (Rott & Agudelo, 2003); that is known to be initiated by the crystallization of uric acid (UA) within the joints. Uric acid is the end product of metabolism of purine. When urates in the blood reach the physiological saturation levels, they crystallize to form monosodium urate (MSU) and gradually accumulate in tissues. This leads to development of asymptomatic hyperuricemia which results into gout (Luk & Simkin, 2005). The clinical manifestations of gout include acute gouty arthritis, deposition of MSU crystals in soft tissues leading to formation of ‘tophi’, urate urolithiasis along with rare incidences of nephropathy. The disease develops in four stages; an asymptomatic hyperuricemia, acute gout with intermittent flares, the intercritical period, and chronic gout (Sundram, 2010). The prevalence of gout have been on a rise during the last few decades chiefly due to changes in life style patterns and increased longevity. In US prevalence has been estimated to be 5.1 million during the period spanning 1988-1994 by the third national health and nutrition examination survey (NHANES III). 5.2 cases per 1000 have been reported by the US managed care database during the year 1999 compared to 2.9 cases in 1990. The disease prevalence rates reportedly are higher in older men than those of rheumatoid arthritis. Incidences of gout have also escalated during the last two decades with annual levels reported by Rochester Epidemiology Project to be twice as high as those reported two decades earlier for primary gout. Higher incidences of disease are reported in men than in women with increased incidences reported with advancing age in both sexes (Weaver, 2008). Despite high prevalence and severe burden of the disease, frequent mismanagement of the disease leads to avoidable incidences of morbidities and mortality (Luk & Simkin, 2005). The current report aims to present an in depth exploration of the risk factors, pathogenesis and treatment modalities of gout. RISK FACTORS Sex Men have a higher level of serum urate rendering them significantly more vulnerable to gout with higher probability of development of gout in men below the age of 30 compared to women of comparable age. The risk of gout development in men peaks in the age range of 75-84 years, while in women the risks are higher during post menopausal phase. After the age of 60, both men and women are equally vulnerable to the disease (Rott & Agudelo, 2003). Diuretics Diuretic intake is a major cause of hyperuricemia since it causes significant enhancement of reabsorption of uric acid in kidney (Rott & Agudelo, 2003). Several other medications such as low dose aspirin, cyclosporine (increases tubular reabsorption of urate), pyrazinamide, ethambutol, and niacin also lead to hyperuricemia (Weaver, 2008). Comorbidities Individuals with hypertension, insulin resistance, cardiovascular diseases, neuropathy, hyperlipidemia, chronic kidney diseases and metabolic syndrome are highly vulnerable to gout (Rott & Agudelo, 2003). Lead exposure has also been found to be associated with gout (Sundram, 2010). Poor urate clearance may render a hemodialysis patient vulnerable to urate deposition and gout. Obesity Individuals with a body mass index (BMI) in the range of 21-22 have been reported to be at much lower risk of developing gout compared to individuals with higher BMI. Alevel of 35 raise the risk three fold. Obesity has been found to be associated with enhance urate synthesis and lower excretion of urate from the kidneys; thereby leading to raised serum urate levels (Weaver, 2008). Dietary Habits A diet rich in meat such as red meat, organ meat; and sea food has been associated with higher vulnerabilities to gout. The same has also been reported for alcohol consumption; especially beer (Choi et al. 2004). On the contrary, purine rich vegetables exhibit no correlation with gout development and dairy products lower the risk marginally (Weaver, 2008). Purine precursors are obtained from both dietary or exogenous sources; and from endogenous sources or metabolic synthesis. Dietary purines are the source of blood uric acids, though the exact quality and quantity of various purines in cooked or processed foods cannot be determined. The dietary purine precursors once ingested, are broken down in to nucleotides by the action of two enzymes; pancreatic nucleases and the phosphodiesterases. Pancreatic and mucosal enzymes then degrade the nucleotides in to bases, phosphates and sugars. Form of purine intake determined the serum levels of uric acid with RNA contributing more than DNA and adenine adding more uric acid than guanine. This could explain the impact of dietary habits on urate levels, thereby rendering certain foods as risk factors for gout and other as not (Choi et al., 2004). Figure 1: Mechanism of Monosodium urate crystal formation and induction of crystal induced inflammation (Choi et al., 2005) SYMPTOMS Gout symptoms include restricted motion of the joint due to acute pain, painful swelling of the joint, redness of the skin at the joint, and inflammation of the affected joint along with other systemic symptoms such as fever, and chills. Acute gout involves intermittent flares with intense pain restricted to specific joint and is self limited (Choi et al., 2005). Incidence of acute pain during acute gouty act is usually preceded by years of asymptomatic hyperuricemia, though not all cases of hyperuricemia develop in to gout. Knees, ankles and feet are the commonly affected joints with approximately 40% of primary incidences being polyarticular. During the intercritical period, gouty attacks are more frequent, longer and involve more intense pain, which if unattended develops in to chronic gout within 6 months to two years. Chronic tophaceous gout on the other hand often results as a consequence of years of acute gout and is characterized by skin exhibiting symptoms of nodular tophi, chronic ulcers and panniculitis. Tophi are usually visible on ears, olecranon bursae, knees and fingers as well as toes in form of firm pink protrusions that ulcerate with oozing out of a chalky substance (Sundram, 2010). Tophi may erode the bones and cartilages, and lead to permanent impairment of movement as a consequence of damage to the skeletal system (Choi et al., 2005). PATHOGENESIS Primary causes of development of gout are not yet understood and due to gout occurrences being frequently associated with a family history of gout; genetic factors are expected to be involved in primary gout occurrence. Genetic polymorphism of urate renal transporters has also been suspected to be critical in development of primary gout (Richette & Bardin, 2010). Secondary gout may develop due to several complex factors including genetic and environmental factors as well as occurrence of other diseases. Recent advances in the understanding of the molecular aspects of gout specifically of the risk factors and molecular mechanisms of urate transport and crystallization have contributed immensely to the understanding of pathogenesis of gout. Uric acid is a weak acid (pKa 5.8) that commonly exists as urate in an ionized form at physiological pH. With the rise in levels of urate the probability of its saturation and crystallization are increased. This accounts for the positive correlation observed between serum urate levels and risk of development of gout (Choi et al., 2005). The silencing of uricase enzymes (present in non-primates and lower primates); in humans as a part of the evolution process leads to gout conditions; a disease exclusively occurring in man. Uricase degrades uric acid to allantoin which is ten times more soluble than former and is therefore easily excreted. However, the conversion process releases hydrogen peroxide, an oxidant. Further higher levels of urate maintained due to absence of uricase ensure reduction of oxidative stress and tissue damage, since uric acid is the chief antioxidant circulating in human system (Terkeltaub, 2007). Urate crystallizes as its monosodium salt in tissue fluids at levels of supersaturation (figure 1). Cation levels along with several other factors such as changes in characteristics of extracellular matrix of the joint leading to rise in levels of nonaggregated proteoglycans, chondroitin sulfate, collagen fibrils etc may also contribute to crystallization of urates since these molecules act as nucleating agents for urates. Further the immediate biochemical environment in the tissue may lead to the dissolution of monosodium urate crystals (MSU) within the tissue fluid. However, if allowed to accumulate the MSU crystals form ‘tophi’ in the synovial fluid and on the cell surface layer of the joint cartilage. The synovial tophi are usually fixed to the wall, but due to changes in uric acid levels of in the synovium or as a consequence of injury; the size and arrangement of urate depositions or tophi is altered. As a consequence ‘crystal shedding’ or the loosening of the tophi from the organic matrix occurs. A loose crystal is able to interact with the synovial cell lining and the inflammatory cells present in the synovium. This interaction leads to the development of inflammation in the affected joint (Choi et al., 2005). Urate levels in the body are dependent on the balance between the levels of dietary intake, synthesis and the rates of excretion from the kidney. Often hyperuricemia results as a consequence of cumulative impact of enhanced synthesis and reduced excretion and rarely due to either overproduction (10-15%) or underexcretion (85-90%) exclusively (Sundaram , 2010). Purine metabolism The de novo synthesis of purine (figure 2) is mediated by the enzymes 5’-phosphoribosyl 1-pyrophosphate (PRPP) synthetase (PRS) and hypoxanthine-guanine phosphoribosyl transferase (HPRT) (de Brouwer et al., 2010). While the former catalyzes the first step to formation of urate from degradation of nucleotides, the latter salvages the purine bases obtained from the degradation of tissue nucleic acids. In approximately 10% of the cases hyperuricemia results as a consequence of the overactivity of PRS or the deficiency of HPRT; i.e. due to inborn errors of metabolism. Overproduction of urate usually results as a consequence of accumulation of ADP and AMP that can conveniently be converted to urate (figure 2). Such conditions are favored in presence of ethanol which on one hand increases ATP degradation, simultaneously reducing renal excretion due to dehydration and metabolic acidosis. Thus beer is found to be an important risk factor for gout. Further the presence of guanosine in beer renders it a bigger risk factor for gout compared to other alcoholic beverages. Another factor affecting the overproduction of urates is fructose, the synthesis of which utilizes ATP. This leads to phosphate depletion, and the resulting AMP becomes available for urate synthesis. Obesity and insulin resistance therefore are risk factors for gout due to involvement of fructose in urate synthesis (Choi et al., 2005). Figure 2: Urate production pathway: gout pathogenesis (Chou et al., 2005) Figure 3: Urate transport mechanism in human proximal tubule (Chou et al., 2005) Renal Urate Transport The urate in the kidney proceeds through glomerular filtration, reabsorption of filtered urate, urate secretion, and finally post secretory reabsorption in renal proximal tubule. Urate transporter 1(URAT-1) is the key transporter controlling the transport of urate ions from lumen to proximal tubular cells and has been established to play a critical role in maintenance of urate homeostasis. Certain agents are known to enhance this transport of urates and are specifically termed as antiuricosurics e.g. diuretics, nicotinate, cyclosporine, lactate and pyrazinoate etc. Certain others i.e. uricosurics reduce the rates of renal transport of urates by inhibiting URAT-1, e.g. probenecid, sulfinpyrazone, losartan etc. Certain other substances such as uricase reduce urate transport through oxidation of urate to allantoin, or allopurinol that inhibits xanthine oxidase. URAT 1 is essential for the activity of both uricosuric and antiuricosuric agents. A secondary sodium dependency also influences urate reabsorption rates by transstimulation mechanism (Enomoto et al., 2002). Exogenous insulin enhances urate reabsorption in the kidney by stimulating URAT1 or by sodium dependent anion cotransporter in the proximal tubules of kidney (Choi et al., 2005). Mechanism of Gout Induced Inflammation Urate crystals are able to initiate an inflammatory response through humoral and cellular inflammatory mediators. They interact with phagocytes in the synovium. The primary mechanism of interaction involves their opsonization and engulfment leading to release of inflammatory mediators. According to the second mechanism the urate crystals interact directly with the phagocyte cell membrane via the glycoproteins present in the membrane thereby initiating a signal transduction pathway. The pathway involves G proteins, phospholipase C, and D, mitogen activated protein kinases ans Src tyrosine kinases. This pathway is responsible for neutrophilic synovitis through expression of interleukin-8 (IL-8) in the monocytic cells that further leads to neutrophil accumulation in synovium. Neutrophilic synovitis is a prominent cause of inflammation in acute gout (Choi et al., 2005). Cellular Aspect of Gout The initial inflammatory responses in gout are attributed to monocytes and mast cells while the neutrophilic accumulation is responsible for inflammation subsequently. Phagocytes containing urates induce an inflammatory response while the macrophages do not. In the former, the urate phagocytosis is followed by synthesis of tumor necrosis factor-? (TNF- ?), and activation of endothelial cells. Monocytes on the other hand generate TNF- ?, IL-?, IL-6, IL-8 and cyclooxygenase 2. Contrary to this macrophages with urate crystals failed to perform either of these actions. Thus it can be concluded that while monocytes play key roles in inflammatory responses in gout, macrophages reverse the inflammatory effect and suppress the symptoms of gout. This aspect of macrophages may be responsible for the self limiting characteristics of acute gout. Acute gout symptoms may also be self-resolved due to inactivation of inflammatory intermediates, release of ntiinflammmatory mediators such as lipoxins, IL-1 receptor antagonists etc (Dalbeth & Haskard, 2005). Chronic gout symptoms may develop as a consequence of mechanisms outlined for acute form of the disease. A long term accumulation of urate leading to chronic inflammation may further contribute to cartilage loss, bone erosion along with chronic synovitis. The tophi produce gelatinase A and gelatinase B which degrade collgen, elastin and gelatin. The expression of gelatinase B is induced by the presence of urate crystals within the macrophages. A dose dependent relationship has been reported in in vitro conditions (Dalbeth & Haskard, 2005). Bone erosion has recently been reported to occur as a consequence of disordered osteoclast development. MSU crystals have been found to affect the RANK Ligand (RANKL)/osteoprotegerin (OPG) balance inside the stroma cells and hence play an indirect role in promoting osteoclastogenesis (Dalbeth et al., 2008). DIAGNOSIS Gout is diagnosed through synovial fluid analysis, blood analysis for the presence of uric acid, joint radiographs, synovial biopsy and presence of uric acid in urine. Chronic gout diagnosis involves calcinosis Curtis, rheumatoid arthritis, and xanthoma. Ultrasound radiography is used to differentiate between tophi and rheumatoid nodules on the basis of variations in echogenicity. Further presence of needle shaped crystals of MSU within the tophi or synovium lead to gout diagnosis. However MSU being water soluble the areas with these needles instead exhibit an amorphous fluffy white material with needle shaped white fissures during biopsy. These fissures are surrounded by histiocytes. The crystals of MSU are clearly visible if an alcohol fixture is used instead of aqueous formalin fixtures during biopsy (Sundaram, 2010). GOUT MANAGEMENT A three phase therapeutic regime is followed for the treatment of gout. The first phase involves treatment of acute attack, which involves methods to control inflammation. Topical ice and rest of the joint are recommended for treatment of acute attacks. Non-steroidal anti-inflammatory agents (NSAIDs) are also used for the treatment of acute pain symptoms. Though highly effective is the treatment initiated within 24 hrs of pain attack, the NSAIDs have been found to produce complications in elderly patients with cardiovascular problems and renal malfunction. They also lead to development of gastric ulcers and may interfere with the effect of other medications being taken simultaneously such as warfarin. Acute attacks can also be treated using colchicines, which though slower than NSAIDs, is safer in individuals with comorbidities and also has a narrower therapeutic index (Sundaram, 2010). Systemic and intra-articular corticosteroids and intramuscular corticotrophin are also used to control inflammation (Schlesinger, 2004). The second phase involves methods to prevent future attacks and rebounds. Hence for the improvement of affected joints intraarticular corticosteroids can be used. NSAIDs and colchicine are used for the treatment of polyarticular joints. When serum uric acid levels are brought down below MSU saturation threshold, the mSU crystals get dissolved. This strategy is being explored for the treatment of gout (Richette & Bardin, 2010). The third phase of treatment involves hypouricemia therapy, which is a long term intervention strategy important for preventing damage to joints, cartilage and kidneys; besides preventing repeated pain attacks. Uricosuric drugs such as allopurinol and probenecid and uricostatic drugs that are xanthine oxidase inhibitors are used for this purpose. These are known to enhance uric acid excretion and reduce serum urate levels. These are long term drugs, continued for life and effectively dissolve the tophi once the serum urate levels are brought under control. This is managed within 6-12 months of treatment (Sundram, 2010). Further management of the disease involves weight control, high fluid intake, alcohol abstinence and a low purine diet. REFERENCES 1 Choi, H. K, D. B Mount and A. M. Reginato. "Pathogenesis of gout." Ann intern medicine (2005): 499-516. 2 Choi, H. K, et al. "Purine rich foods, dairy and protein intake, and the risk of gout in men." N engl J Med (2004): 1093-1103. 3 Dalbeth, N. and D. O. Haskard. "Mechanisms of inflammmation in gout." Rheumatology (2005): 1090-6. 4 Dalbeth, N, et al. "Enhanced osteoclastogenesis in patients with tophaceous gout: urate crystals promote osteoclast development through interactions with stromal cells." Arthritis Rheum (2008): 54-65. 5 de Brouwer, A. P. M, et al. "PRPS1 Mutations: Four Distinct Syndromes and Potential Treatment." Am J Hum Genet. (2010): 506-18. 6 Enomoto, A, et al. "Molecular identification of a renal urate anion exchanger that regulates blood urate levels." Nature (2002): 447-52. 7 Luk, A. J and P. A. Simkin. "Epidemiology of hyperuricemia and gout." Am J Manag Care (2005): S435-S442. 8 Richette, P and T. Bardin. "Gout." Lancet (2010): 318-28. 9 Rott, K. T and C. A. Agudelo. "Gout." JAMA (2003): 2857-60. 10 Schlesinger, N. "Management of Acute and Chronic Gouty Arthritis: Present State-of-the-Art ." Drugs (2004): 2399-2416. 11 Sundaram, U. "Gout." Rongioletti, F and B. R. Smoller. Clinical and pathological aspects of skin diseases in endocrine, metabolic, nutritional and deposition disease. NY: Springer, 2010. 63-8. 12 Terkeltaub, R. "Learning how and when to employ uricase as bridge therapy in refractory gout." The journal of rheumatology (2007). 13 Weaver, A. L. "Epidemiology of gout." Cleveland clinic journal of medicine (2008): S9-S12. Read More