Gout: Pathophysiology, Causes, and Treatment
Gout refers to a type of inflammatory arthritis that develops due to high levels of uric acid in the blood. It is characterized by elevated uric acid levels in blood and urine due to a variety of metabolic abnormalities that lead to the overproduction of uric acid.
Genetic or dietary factors promote increased production or retention of uric acid.
Uric acid has low solubility and easily forms crystalline deposits, preferentially in joints and soft tissue
Urate crystals promote inflammation and lead to arthritis that is painful and destructive
Gout results from excess levels of uric acid which is the end product of adenine and guanine degradation. The disease is not restricted to patients with mutations in a specific gene and can arise from different causes.
It affects mostly middle-aged men (85%), but women become increasingly susceptible to gout after menopause.
Increased PRPP synthetase activity: Increased PRPP synthetase activity results in increased intracellular levels of PRPP.
A partial decrease in HGPRTase activity.
Since there is decreased salvage of hypoxanthine and guanine, PRPP is not consumed by the HGPRTase reaction and PRPP can activate glutamine–PRPP amidotransferase activity.
with decreased salvage of hypoxanthine and guanine, IMP and GMP are not formed via this pathway so that regulation of the PRPP amidotransferase step by IMP and GMP as negative effectors is compromised.
Glucose 6phosphatase deficiency. Loss of glucose 6-phosphatase activity results in more glucose 6-phosphate being shunted to the HMP shunt. Hence more ribose 5-phosphate is generated and the intracellular level of PRPP is in
Factors that promote development of gout
- Overly purine-rich food
- Drugs that contain purines: dideoxyadenosine
- Diuretics such as hydrochlorothiazide and furosemide
- Antituberculosis drugs such as pyrazinamide and ethambutol
- Alcoholic beverages e.g. beer
- Anorexia nervosa
- Drugs that interfere with uric acid excretion: pyrazinamide, salicylic acid
- Excessive fructose or sucrose
Dietary purines are mostly not utilized via salvage pathways but instead are converted to uric acid and excreted.
Anorexia nervosa leads to gout probably due to the formation of ketone bodies, which as organic acids may also increase tubular reuptake of uric acid.
Salicylic acid as well as pyrazinoic acid and hydroxypyrazinoic acid, which are formed in the metabolism of the tuberculostatic drug pyrazinamide, also act as exchange substrates for uric acid and thereby reduce its renal elimination.
Fructose has been linked to increased uric acid production.
Fructokinase enzyme produces fructose-1-phosphate faster than it can be turned over by aldolase. Accumulating Fructose-1-Phosphate ties up phosphate, which is then no longer available for the regeneration of ATP. ADP rises, and adenylate kinase causes AMP to rise in turn; the latter enters degradation to uric acid.
Signs and symptoms
Gout presents most commonly with acute monoarthritis.
As gout becomes chronic it may involve multiple joints,
Deposition of urate crystals in connective tissue (tophi) and kidneys may occur in some cases.
The metatarsophalangeal joint of the first toe is commonly affected (podagra), but other joints such as the knee, ankle, PIPs, or DIPs may be initially involved.
The first episode often occurs at night with severe joint pain waking the patient from sleep; the joint rapidly becomes warm, red, and tender.
The joint pain as a result of gout goes away spontaneously after 3–14 days without any medication
Serum uric acid level is of no value in the diagnosis of acute urate arthropathy. During an acute attack, serum uric acid may be normal or low, but many people with elevated serum uric acid never develop gout. The diagnosis is made by analysis of synovial fluid instead.
On synovial fluid analysis, the MSU crystals are negative birefringent and needle-shaped. WBCs will range from 5000–50,000.
X-ray of a joint that has been involved in multiple gouty attacks will show erosive calcifications.
Treatment of gout
The goal of treatment in patients with acute gouty arthritis is to decrease inflammation and thus prevent erosion and destruction of the joint also in this stage, it is very important to avoid fluctuations in serum uric acid level.
Nonsteroidal antiinflamatory drugs
Oral steroid medications can be used in elderly patients.
NSAIDs/colchicine or in patients with renal impairment
Colchicine is rarely to be used in acute gout but is still available
Allopurinol inhibits xanthine oxidase and thereby the formation of uric acid.
Do not initiate allopurinol during an acute crisis of gout. However, if a patient has been taking allopurinol and an acute attack occurs, do not discontinue.
Allopurinol can be used in overproducers, undersecretors, or patients with renal failure or kidney stones
Febuxostat is used in those intolerant of allopurinol.
Pegloticase dissolves uric acid: used in refractory disease
Probenecid can be used in the undersecretors (>80% of adults) only. Rarely used today
Benzbromarone is a uricosuric drug that works by inhibiting the tubular reuptake of uric acid by URAT1. URAT1 is the key transporter in tubular reuptake which exchanges uric acid for other organic acids. By so doing it increases renal elimination of uric acid.
In gout inhibition of xanthine oxidase prevents the final oxidation steps, leading to the excretion of uric acid.
Hypoxanthine and xanthine are somewhat more soluble than uric acid and therefore less prone to precipitation prior to excretion.
With chronic hypouricemic gout, the goal is to decrease uric acid levels. This is usually required for life and initiated in those whose recurrent gouty attacks cannot be corrected by low-purine diet, alcohol limitation, avoiding diuretics, etc.
Application of urate oxidase (uricase) comes in handy in the treatment of gout.
This enzyme, which occurs in animals other than primates and in many other organisms, converts urate to allantoin, which is considerably more soluble and forms the end product of purine degradation in these organisms.
Rasburicase medication is a recombinant urate oxidase that used to cope with excess urate in chemotherapy patients.
It is an alternative to oral allopurinol for managing hyperuricemia in cancer patients (primarily lymphoma or leukemia)
An acute increase in plasma levels (e.g., after cancer chemotherapy result in tumor lysis and subsequent elevation of plasma uric acid) results in acute renal failure due to the precipitation of urate in renal tubules.