Gout Disease - Human & Disease

Gout Disease


 What is gout? 

Gout is a disease in which tissue deposition of monosodium urate (MSU) crystals occurs as a result of  hyperuricemia, resulting in one or more of the following manifestations:

 • Gouty arthritis.

 • Tophi

 (aggregated deposits of MSU occurring in osseous, articular, cartilaginous, or soft tissue areas).

 • Gouty nephropathy.

 • Uric acid nephrolithiasis.

The term gout is derived from the Latin word gutta, which translates as “a drop”. In the 13th century, it was thought that gout resulted from a drop of evil humor affecting a vulnerable joint. This explains why a majority of early gout therapies were aimed at removing excess humor (e.g., the use of bloodletting and cupping).

Gout is a disease in which tissue deposition of monosodium urate (MSU) crystals occurs as a result of hyperuricemia, resulting in one or more of the following manifestations: • Gouty arthritis. • Tophi (aggregated deposits of MSU occurring in articular, osseous, cartilaginous, or soft tissue areas). • Gouty nephropathy. • Uric acid nephrolithiasis. The term gout is derived from the Latin word gutta, which translates as “a drop”. In the 13th century,
Gout






 



How is hyperuricemia defined?

 What are the most common factors associated with hyperuricemia and gout?

Hyperuricemia is defined by a serum urate concentration exceeding its solubility threshold, promoting the formation and deposition of MSU. At a physiologic pH, hyperuricemia is defined as a serum concentration >6.8 mg/dL (>360 μmol/L). Serum urate concentrations increase with age and are higher in men than in women, increasing in association with the onset of puberty in young men and menopause in women (the latter owing to uricosuric properties of estrogen). Gout is rare in men aged <25 years and in premenopausal women; when it occurs in these populations, it is often attributed to an inherited defect in purine metabolism, alcohol use, and/or renal insufficiency including familial juvenile hyperuricemic nephropathy or medullary cystic kidney disease. In addition to older age and male sex, other factors commonly associated with hyperuricemia and gout include obesity, hypertension, and other elements of metabolic syndrome, high purine intake, a family history of gout, alcoholism, renal insufficiency, the use of selected medications such as low-dose aspirin, diuretics, and cyclosporine among others.

Gout is a disease in which tissue deposition of monosodium urate (MSU) crystals occurs as a result of hyperuricemia, resulting in one or more of the following manifestations: • Gouty arthritis. • Tophi (aggregated deposits of MSU occurring in articular, osseous, cartilaginous, or soft tissue areas). • Gouty nephropathy. • Uric acid nephrolithiasis. The term gout is derived from the Latin word gutta, which translates as “a drop”. In the 13th century,
Gouty-Arthritis







How prevalent is gout? 

The overall prevalence of gout in the United States is estimated to be 3.9% (affecting 5.9% of men and 2% of women and affecting a total of 8.3 million individuals), representing by far the most common form of inflammatory arthritis. Hyperuricemia is a necessary, but not sufficient, risk factor in gout onset and is seen in approximately one of every five adults in the United States. Although only a small proportion of individuals with hyperuricemia eventually develop gout (∼15%), the risk increases to >20% in the context of marked hyperuricemia (e.g., >9–10 mg/dL). 

The risk of gout increases with advancing age and parallels age related increases in serum urate. 

The frequency of gout in those aged >80 years is >30-fold higher than in those aged between 20 and 29 years. It has been estimated that the prevalence of gout has increased by almost 50% in the last few decades alone, an increase that appears to be in part related to rising rates of obesity.

Gout is a disease in which tissue deposition of monosodium urate (MSU) crystals occurs as a result of hyperuricemia, resulting in one or more of the following manifestations: • Gouty arthritis. • Tophi (aggregated deposits of MSU occurring in articular, osseous, cartilaginous, or soft tissue areas). • Gouty nephropathy. • Uric acid nephrolithiasis. The term gout is derived from the Latin word gutta, which translates as “a drop”. In the 13th century,
Sodium-Ureate-Crystals







 Uric acid is a product of the metabolism of which group of nucleotides?

Uric acid is the end-product of purine degradation. Humans lack the enzyme uricase, which in other species oxidizes uric acid (low solubility) to the highly soluble compound allantoin. The lack of this enzyme subjects humans to the potential risk of tissue deposition of MSU crystals. Although humans possess the uricase gene, it is inactive. It is postulated that humans have acquired the propensity to become hyperuricemic because uric acid may exert potent antioxidant properties

Gout is a disease in which tissue deposition of monosodium urate (MSU) crystals occurs as a result of hyperuricemia, resulting in one or more of the following manifestations: • Gouty arthritis. • Tophi (aggregated deposits of MSU occurring in articular, osseous, cartilaginous, or soft tissue areas). • Gouty nephropathy. • Uric acid nephrolithiasis. The term gout is derived from the Latin word gutta, which translates as “a drop”. In the 13th century,
Gout-Foot-Pain




What pathogenic processes are responsible for the development of hyperuricemia?

 • Overproduction of urate (endogenous or exogenous dietary purine precursors).

 • Underexcretion of urate (abnormal renal handling of urate).

 • A combination of both processes.

Most patients with hyperuricemia and gout are underexcreters of uric acid (90%).


How do you determine if a patient with gout is an overproducer or underexcreter of uric acid?

Although not routinely required in clinical management, a 24-hour urine collection can be obtained to determine uric acid and creatinine excretion (the latter to ensure an adequate 24-hour collection). On a regular purine diet, a urate value >800 mg/24 hours suggests overproduction, whereas a value <800 mg suggests underexcretion.

Gout is a disease in which tissue deposition of monosodium urate (MSU) crystals occurs as a result of hyperuricemia, resulting in one or more of the following manifestations: • Gouty arthritis. • Tophi (aggregated deposits of MSU occurring in articular, osseous, cartilaginous, or soft tissue areas). • Gouty nephropathy. • Uric acid nephrolithiasis. The term gout is derived from the Latin word gutta, which translates as “a drop”. In the 13th century,
Gouty-Arthritis





The two inherited enzyme abnormalities in the urate biosynthesis pathway that can cause urate overproduction:

 • Overactivity of phosphoribosylpyrophosphate (PRPP) synthetase.

 • Partial deficiency of hypoxanthine–guanine phosphoribosyltransferase (HGPRT) (Kelley-Seegmiller syndrome).

These enzyme abnormalities, which cause urate overproduction, are inherited as X-linked traits. Men with these abnormalities often present with early-onset gout (<25 years of age) and a high incidence of uric acid nephrolithiasis. Complete HGPRT deficiency results in Lesch-Nyhan syndrome (mental retardation,spasticity, choreoathetosis, and self-mutilation). Furthermore, patients with glucose-6-phosphatase deficiency (von Gierke’s disease) also exhibit urate overproduction due to an accelerated ATP breakdown during hypoglycemia-induced glycogen degradation. Inhibition of renal tubular urate secretion can also occur in this disease as a result of competitive anions from lactic acidosis. Finally, patients with hereditary fructose intolerance caused by fructose-1-phosphate aldolase deficiency can develop hyperuricemia in part because of accelerated ATP 


What are the acquired causes of hyperuricemia?

- Urate overproduction: excess dietary purine consumption, accelerated hepatic ATP degradation in alcohol abuse or fructose ingestion, and increased nucleotide turnover in myeloproliferative and lymphoproliferative disorders.

- Urate underexcretion: renal disease, lead nephropathy (saturnine gout), inhibition of tubular urate secretion (keto- and lactic acidosis), select drugs (see Question 9), and miscellaneous causes such as hyperparathyroidism,hypothyroidism, and respiratory acidosis.

Gout is a disease in which tissue deposition of monosodium urate (MSU) crystals occurs as a result of hyperuricemia, resulting in one or more of the following manifestations: • Gouty arthritis. • Tophi (aggregated deposits of MSU occurring in articular, osseous, cartilaginous, or soft tissue areas). • Gouty nephropathy. • Uric acid nephrolithiasis. The term gout is derived from the Latin word gutta, which translates as “a drop”. In the 13th century,
Gout-Arthritis







 The drugs that cause hyperuricemia due to decreased renal excretion of urate:

The mnemonic CAN’T LEAP can be used to remember these drugs:

. Cyclosporine

. Alcohol

. Nicotinic acid

. Thiazides/Tacrolimus

. Lasix (furosemide) 

. Ethambutol

. Aspirin (low dose)

. Pyrazinamide

Other drugs that can cause hyperuricemia include levodopa, theophylline, and didanosine. 

In contrast, the following commonly used drugs exert mild uricosuric effects and produce modest urate lowering: 

amlodipine, atorvastatin, fenofibrate, leflunomide, losartan, rosuvastatin, and high-dose salicylates.


excessive alcohol consumption often lead to hyperuricemia and gout:

The quantity of alcohol consumption strongly correlates with the risk of developing gout. Consuming over 30 to 50 g of alcohol a day (three to four beers, glasses of wine, or liquor shots) increases gout risk by 2 to 2.5-fold compared with someone who does not consume alcohol. Alcohol consumption increases urate synthesis by accelerating the hepatic degradation of ATP. Alcohol consumption is also associated with lactate production, which further reduces renal urate excretion. In addition to alcohol content, beer contains a substantial amount of the purine guanosine and confers a >2-fold risk of gout over liquor. Moderate wine consumption does not appear to increase serum urate or gout risk. Recent data suggests that among those with established gout, episodic consumption of all alcohol types (wine, beer, and liquor) increases the risk of recurrent flareof the gout attacks.


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