The connection between hyperuricemia, gout and B12

Hyperuricemia is defined as elevated uric acid in the extracellular fluids and tissues. This is most commonly due to impaired excretion of uric acid via the kidneys, but can also be due to increased uric acid production.¹

Around 85-90% of people with hyperuricemia are asymptomatic, but chronically elevated uric acid levels can lead to gout or nephrolithiasis (kidney stones) over time.²

Serum uric acid levels are typically considered elevated when they exceed ~7.0 mg/dL in men and 6.0 mg/dL in women.

Uric acid becomes less soluble at concentrations above ~6.8 mg/dL, which increases the risk of crystal formation.
 

(note that reference ranges may vary between laboratories.)

• Solubility threshold: ~6.8 mg/dL (key physiologic reference)
• Hyperuricemia commonly defined as 7.0 mg/dL in men and 6.0 mg/dL in women.³

Up to 21% of the general population is estimated to have asymptomatic hyperuricemia. Someone may have high uric acid levels for many years before they develop gout, but some never do.⁴

Gout is a type of inflammatory arthritis and the most common manifestation of hyperuricemia due to the deposition of uric acid crystals in the joints. Symptoms include sudden, very painful swelling of the joints, most often the base of the big toe, but can also affect the midfoot and ankle joints, knees, elbows, wrists and knuckles. Joints become swollen, red, and sensitive. Swelling typically dissipates after a few days, and the skin around the joint may begin to peel.

Chronic gout can lead to inflammation in other joints (arthritis), potentially damaging cartilage and bone, which can affect mobility.

An estimated 50-60% of patients with chronic kidney disease (CKD) have hyperuricemia, largely due to poor renal excretion of uric acid. While the deposition of urate crystals can occur in some cases, hyperuricemia is usually a result of impaired kidney function, rather than CKD itself.⁵

Early CKD is initially asymptomatic (stages 1-3 are typically asymptomatic), and symptoms may not appear until stages 4 or 5. Common symptoms and signs at these stages may include nausea, vomiting, loss of appetite, fatigue and weakness, low urine output, swelling in the feet and ankles and persistently itchy skin.⁶

Common causes of high uric acid include:

• Diet
  Eating a diet high in purines can lead to excess uric acid in the body. Purines are natural chemical compounds made of nitrogen and carbon that the body breaks down into uric acid. Foods high in purines include organ meats (liver, kidney), red meats and seafoods (especially shellfish).
  Fructose also increases uric acid production by accelerating purine breakdown in the liver and depleting cellular energy stores, which increases uric acid synthesis.⁷
  Alcohol consumption is one of the major dietary risk factors for high serum urate levels.
  The ethanol in alcoholic beverages increases uric acid production and decreases the elimination of uric acid to urine by modulating kidney tubule function. Other ingredients in alcoholic beverages (e.g., purines) can also affect serum urate levels, so different beverages can affect serum urate levels differently.
  Common triggers include beer, sake (rice wine), shochu (Japanese spirit), wine and whiskey.
  
  
• Genetics
  A strong genetic link exists (ABCG2 dysfunction) in the development of hyperuricemia as compared to environmental risk factors such as obesity, aging and heavy alcohol drinking.
  ABCG2 (ATP-binding cassette subfamily G member 2) is a urate transporter involved in the excretion of uric acid via the kidneys and digestive system, and its dysfunction can lead to elevated serum uric acid levels.⁸
   
• Medications
  Medications associated with increased uric acid levels include diuretics, low-dose aspirin and cyclosporine.
  
  
• Health conditions
  Hypertension, hypothyroidism, obesity and insulin resistance are also linked to increased uric acid levels.

Avoid or limit:

These foods are associated with higher uric acid levels and increased risk of hyperuricemia.

• High-purine foods
  Organ and offal meats: Liver (beef, chicken, pork), kidneys, sweetbreads (thymus/pancreas), heart, brain, tripe
  Red meats: Beef, lamb, pork, venison, mutton, goat
  Seafood: Anchovies, sardines, mussels, scallops, shrimp, crab, lobster, herring, mackerel, trout, tuna, fish roe (caviar)
  
  
• Alcoholic beverages
  Beer: highest impact on uric acid increases (contains purines and inhibits excretion)
  Spirits (vodka, whiskey, etc.)
  Wine: lower risk than beer but still contributes if consumed frequently
  
  
• High-sugar and high-fructose foods
  Sodas, fruit drinks sweetened with high-fructose corn syrup
  Sweetened juices and energy drinks
  Candy, baked goods high in added sugar
  Some fruit juices with concentrated fructose

Eating a low-purine diet and avoiding alcohol, particularly beer and spirits, sugar-sweetened beverages, heavy meals and excessive intake of meat and seafood has been shown to reduce uric acid levels by around 10-15%.⁹

Increase intake:

• Low-purine protein foods
  Low-fat dairy products: skim milk, low-fat yogurt, kefir
  Soy/plant proteins: tofu, tempeh, edamame
  Eggs
  Nuts/seeds
  
  
• Fruits and vegetables
  Cherries and berries: associated with fewer gout flares and lower inflammation (anthocyanins). 
  Brightly coloured fruits, including citrus; leafy greens and most veggies high in vitamin C and antioxidants
  
  
• Whole grains/high fibre foods
  Brown rice, oats, quinoa, barley
  Legumes (beans, lentils, peas): Note that although legumes have moderate purine levels, evidence indicates they do not increase gout risk and are considered safe and beneficial.
  
  
• Hydration
  Water. Increased intake of water assists in flushing excess uric acid from the body. Some evidence suggests that higher urine pH may reduce uric acid stone risk, though data on alkaline water is limited.¹⁰
  Coffee: observational evidence suggests coffee may lower the risk of gout, possibly due to increased uric acid excretion.
  
  
• Exercise
  Regular exercise and maintaining healthy weight are both shown to be preventive measures for gout.

Observational studies have shown associations between higher intake of vitamin B12 and folate and a reduced risk of gout. These associations are attributed to mechanisms involving uric acid production, excretion, and the inhibition of inflammation and oxidative stress. 

It has been suggested that folate and its derivatives may inactivate xanthine oxidoreductase (XOR), which is essential for converting hypoxanthine to xanthine and xanthine to uric acid. By binding with XOR, folate may help to impair the conversion process.¹⁶

Studies also show that high homocysteine increases S-adenosylhomocysteine, which releases increased purine nucleotides and the production of uric acid. Folate and vitamin B12 lower homocysteine by converting it to methionine. Lower homocysteine is associated with reduced risk of hyperuricemia.¹⁷

There is a significant correlation between elevated urate levels and the development of kidney stones. 

Uric acid is the end product of purine metabolism. Crystals form when levels exceed the body’s ability to metabolise uric acid, which can result in either gout or kidney stones depending on where they form. Uric acid kidney stones develop when urinary pH is too acidic (usually less than 5.5). Around 5-10% of kidney stones are pure uric acid. Unlike monosodium urate crystals in gout, these kidney stones are composed of uric acid itself. The formation of kidney stones depends on urine acidity and concentration, rather than body’s total uric acid levels.¹⁸

In gout, uric acid crystallizes as monosodium urate (MSU) in joints and surrounding tissues when serum levels typically exceed 6.8 mg/dL. This occurs when MSU crystals are deposited in synovial fluid and cartilage, triggering intense inflammation and symptoms of gout, usually starting in the big toe.