Thursday, December 31, 2015

Gout

Uric Acid and Gout

Gout is a disease that involves the accumulation monosodium urate crystals in synovial fluid or soft tissues due to high uric acid levels.  These monosodium urate crystals are ingested by immune cells, which trigger an inflammatory response* that leads to pain [1].  Uric acid levels are associated with gout (see graph below) [2] and reducing uric acid levels to ≤ 6mg/dl lowers the risk and symptoms of gout [3]


Uric acid levels become elevated when the demand of uric acid excretion exceeds the capacity of the kidney to excrete uric acid [4].  A high dietary purine intake (discussed below) is a main factor that increases excretion demand, while impaired kidney function is the main factor that would decrease excretion capacity.  Kidney function tends to decline with age, with some of this decline in function probably just being normal aging, but there are also many factors that impair kidney function that largely apply to older people.  These include pre-diabetes and type 2 diabetes [5] (insulin also reduces uric acid clearance [6]), cardiovascular disease [7], hypertension [8], diuretics [9] and low dose aspirin [10]

* The role of inflammation makes sense given the cyclical pattern of symptom severity in accordance with the circadian rhythm.  Gout tends to be worse in the evening/night and the least painful in the morning, which corresponds to the circadian rhythm regarding inflammatory cytokines (higher cortisol in the AM and higher IL-6, melatonin, growth hormone and leptin in the evening).  Treatments that reduce inflammation would be expected to improve symptoms but probably won’t address the underlying cause

Diet and Lifestyle Risk Factors

Reviews of observational studies [2] [11] [12] found that several things are associated with gout including:

·         Diet (see this table)
o   Alcohol
o   Sugar sweetened beverages and fruit juice (but no mention of evidence regarding fruit)
o   Purine rich foods such as meat and fish, but not total protein intake
o   Dairy foods and coffee are inversely associated with gout
·         Other chronic diseases such as:
o   Cardiovascular diseases
o   Metabolic syndrome and type 2 diabetes
o   Obesity
o   Kidney disease
·         Some classes of drugs:
o   Diuretics
o   Aspirin
o   Beta-blockers
o   ACE inhibitors

Most of these aren’t particularly surprising considering what I mentioned above

* Vitamin C intake of >1500 mg was associated with a lower incidence of gout (RR = 0.55) in the HPFS [2].  A meta-analysis of RCTs found that vitamin C supplementation (median dose = 500 mg) reduces uric acid in people with normal uric acid levels and without gout [13].  However, a clinical trial on people with gout found that vitamin C supplementation (500 mg) had no effect on uric acid levels [14] (this trial had 40 participants (good enough) and I didn’t notice any similar trials to confirm this result)

Purines

Purines are organic compounds that contain that contain those two nitrogen and carbon based rings.  Adenine and guanine are nucleotides which are part of DNA and RNA (uracil for guanine).  They are converted to hypoxanthine by purine nucleoside phosphorylase, and then xanthine oxidase converts hypoxanthine to xanthine and xanthine to uric acid.  As a result a high purine diet could increase uric acid and lead to gout, especially once kidney function has become impaired.  Foods rich in purines include: meat, fish, organ meats, legumes, some vegetables, coffee and chocolate.  Foods low in purines include grains and dairy [15].  Allopurinol, a drug used in the treatment of gout, reduces uric acid by inhibiting xanthine oxidase


A PubMed search of ‘purine diet gout’ for clinical trials only turned up two papers.  The first study found that a purine free diet doesn’t significantly reduce uric acid and purine levels in people with gout (the purine free diet was isocaloric, lower in fat (20% vs. 25%) and “purine-rich foods were rigorously eliminated, such as meat, fish, salads, eggs, sausages, legumes, chocolate, alcohol, tea, coffee and Coca Cola; noodles, bread, cheese, dairy products, fruit and vegetables were allowed“) [16].  The second study found that advice that an education program that recommended “(i) reducing red meat intake, and avoiding offal, shellfish and yeast extract; and (ii) including low fat dairy products, vegetables and cherries and the potential benefit of coffee and vitamin C” improved participants’ knowledge, but didn’t lower uric acid levels (whether they followed the advice is unknown) [17].  I’ll do some broader searches and write a blog post if I find anything interesting

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