Historical Perspective

Believe it or not, gout – previously called ‘the disease of the kings’ or arthritis of the rich as opposed to rheumatism – arthritis of the poor! – was first described by the Egyptians (when it was known as podagra) in 2640 BC. It was later recognised by Hippocrates in the 5th century BC, who referred to it as ‘the unwalkable disease’ and went on to describe its presentation and disease course in striking detail – most of his clinical perceptions of the conditions are still as relevant today as they were 2,500 years ago (Nuki & Simkin, 2006; Star & Hochberg, 1993)! Talk about being ‘ahead of time’!

Modern day Prevalence of the Disease

In more recent times, gout and hyperuricemia (raised uric acid levels in blood), have shown a steady rise in prevalence and incidence (doubled), especially in the US (Choi, Atkinson, Karlson, Willett, & Curhan, 2004; Choi & Curhan, 2008; Roubenoff et al., 1991). Population studies have reported the incidence of gout in much of the developed world to range between 1-2% (Richette & Bardin, 2010); incidence of hyperuricemia may be as high as 15-20% (Doherty, 2009; Mikuls et al., 2005). Males are more likely to be affected – 80% of cases of gout in Northern Europe tended to be men (Annemans et al., 2008; Doherty, 2009). It is the commonest inflammatory arthritis in men (Choi et al., 2004; Choi & Curhan, 2008; Richette & Bardin, 2010; Roubenoff et al., 1991) and the most common inflammatory arthritis in older women (Doherty, 2009). Prevalence increases with age, in both sexes (Doherty, 2009; Star & Hochberg, 1993). Age and gender specificity of the condition explains the rarity of the conditioning in young, pre-menopausal women (Doherty, 2009; Wallace, Riedel, Joseph-Ridge, & Wortmann, 2004).

Natural Course of the Disease

Gout / gouty arthritis refers to an acute attack of inflammatory arthritis, provoked by the release of monosodium urate (MSU) crystals into joint spaces. Natural course of the disease (Doherty, 2009; Richette & Bardin, 2010, 2012; Wallace et al., 2004) is characterised by 3 distinct phases:

  1. Asymptomatic hyperuricemia (raised serum uric acid – sUA),
  2. Episodes of acute attacks, and
  3. Asymptomatic, inflammation/pain-free intervals and progression on to chronic gouty arthritis

Characteristic presentation of an acute attack is typically an inflamed base of (usually) the big toe (the first metatarsophalangeal – MTP – joint), with warmth, redness and pain. Rarely, other joints may also be involved.

Pathogenesis: The Conventional View

There is no denying that diet does play a crucial role in prevention and treatment of gout. Traditionally, hyperuricemia – resulting from an increased production of uric acid (due to increased purine breakdown after ingestion of purine-rich, animal-based, proteinaceous foods) has been suggested to be majorly causative of gout. In humans, uric acid is the final metabolite of both dietary and endogenously produced purine metabolism (Richette & Bardin, 2012). Sometime during the Miocene period, it is believed that human beings lost the ability to produce an enzyme called ‘uricase’ , which is normally responsible for converting the insoluble uric acid into highly soluble, allantoin (Doherty, 2009). When the accumulation of uric acid (98% of which is present in ionic form) crosses a saturation point, it combines with Na+ in the extracellular spaces and forms MSU crystals and precipitates into joint spaces leading to gout (Richette & Bardin, 2010, 2012). Not surprising then, that avoiding purine-rich foods – meats, poultry, fish, soy and non-soy legumes – with the aim of reducing sUA, is the standard dietary advice given and followed. Conventional pharmaceutical approach (urate lowering therapy – ULT), through the use of drugs like allopurinol, also aims to reduce sUA (Richette & Bardin, 2012). That said, there seem to be some major problems with this hypothesis at all levels:

  1. Although, high intake of purine-containing foods does indeed increase the risk of urate deposition, and increases up to five-fold, the risk of gout attack amongst known patients, how it does so, still remains a query (Zhang et al., 2012)
  2. Meat-eaters will typically have other confounding factors as well – a diet high in sugar, sweetened beverages, refined grains, processed meats and low ingestion of fruits and veggies, not to mention cigarette smoking and ingestion of alcohol (which itself increases uric acid levels – more on this later)
  3. Purine-rich vegetarian foods do not seem to increase the risk – it has been reported that dietary intake of soy and non-soy legumes reduces the risk of gout (Teng, Pan, Yuan, & Koh, 2015)
  4. In rare cases, gouty arthritis can develop in patients with no history of hyperuricemia (McCarty, 1994; Urano et al., 2002)
  5. It is not the sUA per se but the rapid dissolution of already formed urate deposits and precipitation of MSU crystals in the joint spaces is what triggersan acute attack of gout (Richette & Bardin, 2012) – attacks during the first few months of initiation of a ULT supports this notion
  6. Although mechanisms vary, other factors or conditions can also lead to an acute attack through lowering of urate levels: systemic inflammation, ingestion of whiskey and post-surgery. Alcohol intake is associated with both increased endogenous urate production (Bleyer & Hart, 2006) and rapid, transient decrease in sUA through its uricosuric (increased renal excretion of uric acid) actions
  7. Release of pro-inflammatory molecules, cytokines and interleukins (IL-6), which are a hallmarks of systemic inflammation, have been shown to stimulate the hypothalamo-pituitary-adrenocortical axis leading to release of cortisol (Dunn, 2000; Wang & Dunn, 1999). It is suggested that cortisol may be secreted through the same mechanism in gouty arthritis too. Cortisol has a uricosuric effect (McCarty, 1994) and thus, may contribute to an acute attack of gout
  8. 20-25% of asymptomatic patients with sUA exhibit MSU crystal deposits in their joints – especially the knees and the first MTP joint (Pineda et al., 2011; Puig et al., 2008; Richette & Bardin, 2012) and yet do not suffer from attacks of gout – suggesting that other factors must be at play
  9. There is ample evidence to suggest that genetic factors, obesity (especially, during early adulthood) and systemic inflammation contribute significantly to gout (Bleyer & Hart, 2006; Roubenoff et al., 1991; Teng et al., 2015; Urano et al., 2002). And, a serious discussion on these factors by the research community is long overdue.
  10. Genetic and other metabolic disorders (suggestive of systemic inflammation) occur concurrently with gout: obesity, diabetes, chronic renal failure, to name a few

The Fructose Connection

Whereas fructose from natural sources seem to be benign, there is some evidence to suggest that higher intake of fructose – especially, through artificial sources (high-fructose corn syrup and excess of table sugar), may produce metabolic anomalies, including hypertriglyceridemia and sUA (Angelopoulos et al., 2009). Fructose does this through both increased endogenous production and reduced renal excretion (Nakagawa et al., 2006).

Take Home Message

  1. Not enough evidence that avoiding meats will reduce uric acid levels or likelihood of an acute attack of gout
  2. Raised uric acid levels, by themselves may not be responsible for an acute attack of gout
  3. If you already have hyperuricemia, beware of factors or conditions that cause sudden reduction in serum uric acid levels – avoid alcohol
  4. Fructose from artificial sources (including but not limited to, sweetened beverages) should be avoided
  5. Reduction of system inflammation (weight loss, paleo / keto diet) may help


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