PharmaNutrition 3 (2015) 29–45

Contents lists available at ScienceDirect

PharmaNutrition
journal homepage: www.elsevier.com/locate/phanu

Review

Roles of diets and dietary factors in the pathogenesis, management and

prevention of abnormal serum uric acid levels
Christopher E. Ekpenyong * , Nyebuk Daniel
Department of Physiology, Faculty of Basic Medical Sciences, University of Uyo, Uyo, Nigeria

A R T I C L E I N F O A B S T R A C T

Article history: Diet plays an important role in the pathogenesis of abnormal serum uric acid (UA) levels and associated
Received 1 September 2014 complications. Diet modification has been universally adopted as an important and early intervention
Received in revised form 9 December 2014 approach to reduce or increase UA production and/or enhance or inhibit UA excretion. This article reviews
Accepted 15 December 2014
the literature on the effects of diets and dietary factors on serum UA levels. The most recently published
Available online 18 December 2014
studies make dietary recommendations aiming to modulate UA levels, including the consumption of low-
fat dairy products, whole grains, vegetables, fruits, nuts, legumes, vitamin C, and coffee as well as the
Keywords:
moderation of sugary foods, meats and meat products, seafood, and sugar-sweetened beverages.
Diet
Hyperuricemia
Individuals with gout should avoid consuming organ meats, sweet breads, high fructose corn syrup,
Gout sweetened beverages, and alcohol and should avoid alcohol altogether during periods of frequent gout
Prevention attack. Serving sizes of meat and meat products, seafood, table sugars, sweetened beverages, table salt,
Management and alcohol should be limited, whereas low-fat or non-fat dairy products and vegetables should be
encouraged. Dietary intervention remains the only non-pharmacological approach for the long-term
prevention, control, and management of abnormal serum UA levels and associated complications in
humans.
ã 2014 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2. Physiology of UA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3. Food sources affecting serum UA concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.1. Food sources modulating serum UA concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.1.1. Vegetables, fruits, whole grains, legumes, and nuts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.1.2. Caffeinated and decaffeinated coffee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3.1.3. Dairy foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3.1.4. Cherries and cherry products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.1.5. Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.1.6. Urine-alkalinizing/acidifying foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.2. Foods that increase serum UA levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.2.1. Meat, meat products, and seafood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.2.2. Beer and spirits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.2.3. Fructose and fructose-sweetened beverages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.3. Effects of macronutrients on serum UA levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.3.1. Complex versus simple carbohydrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.3.2. High-fat versus low-fat diets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.3.3. Fish and plant oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.3.4. Protein-rich foods and food products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

* Corresponding author. Tel.: +23 48023347719/67548487.

E-mail addresses: [email protected], [email protected]
(C.E. Ekpenyong).

http://dx.doi.org/10.1016/j.phanu.2014.12.001
2213-4344/ ã 2014 Elsevier B.V. All rights reserved.
30 C.E. Ekpenyong, N. Daniel / PharmaNutrition 3 (2015) 29–45

3.3.5. Proportions of macronutrient intake . . ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

3.4. Effects of electrolytes and mineral on serum UA levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.4.1. Potassium and magnesium . . . . . . . . . ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.4.2. Sodium . . . . . . . . . . . . . . . . . . . . . . . . . ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.4.3. Calcium . . . . . . . . . . . . . . . . . . . . . . . . . ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

1. Introduction system pathologies. The negative effects of gluttony in the

pathogenesis of perturbed serum UA levels and the importance
The global incidences of hyperuricemia and gout in the general of dietary restraint have been documented since ancient times
population are increasing [1–5]. These disorders commence earlier [2,23,24].
in younger generations [6–8]. This may indicate the burden of A growing body of evidence indicates changes in dietary habits
metabolic syndrome clusters associated with hyperuricemia will can lead to abnormal serum UA concentrations and associated
be greater in the future, because current risk factors eventually complications either directly affecting production owing to high
manifest as disease and public health burdens. Serum uric acid purine-containing diets or indirectly owing to dietary-related
(UA) concentration is determined by the balance between purine insulin resistance, which affects renal UA processing by either
intake and UA production with UA elimination via the renal and inhibiting secretion or enhancing reabsorption [25]. In addition,
extra-renal routes. Approximately one-third of total body UA the causal role of insulin resistance in the pathogenesis of
comes from dietary purines, while the other two-thirds is comorbidities (i.e., obesity, hypertension, dyslipidemia, type
produced endogenously [9]. The kidneys excrete approximately 2 diabetes mellitus, and chronic kidney disease) that promote
65–75% of UA produced daily, while the remaining 25–35% is hyperuricemia is well documented [26–29]. Therefore, diet is the
eliminated via the intestinal routes to maintain normal serum UA major lifestyle change that is driving the increasing prevalence of
levels [10]. Therefore, abnormal serum UA levels (<2 or >7 mg/dL hyperuricemia [30].
for males and <2 mg/dL or >6.5 mg/dL for females) ensue if In the 5th century BCE, Hippocrates acknowledged the role of
production or renal excretion is affected. The causal roles of excessive food and wine intake in the pathogenesis of abnormal
genetic, lifestyle (e.g., westernized diet and alcohol consumption), serum UA concentration and gout, and recommended dietary
and environmental factors in the pathogenesis of hyperuricemia restriction and reduction of alcoholic beverages for prevention as
and gout are cumulative [11–15]. The increasing trend of UA levels well as large doses of hellebore as treatment for acute attacks
and hyperuricemia prompted investigations of the changes in [9,24]. Concordantly, findings from recent epidemiological studies
genetic, lifestyle, and environmental factors that responsible for support dietary modifications for the management of abnormal
this persistent trend. This scenario is thought provoking when serum UA levels. To date, these recommendations have been
considering the fact that previous generations may not have largely ignored by modern society [31] as a result of the
experienced some of the metabolic disorders associated with globalization of food patterns and inconsistent research findings,
abnormal serum UA levels experienced today; they may have lived leading to uncertainty regarding the role of diet in the etiology of
simple but healthy lifestyles, eating simple yet nutritious diets that abnormal serum UA concentrations [9,32–34]. This article provides
resulted in healthier serum UA levels and longevity. an overview of the current understanding of how diet influences
Available evidence suggests humanity’s problems started serum UA concentration and explains how such effects could be
approximately 10–20 million years ago, when for unexplained exploited in the prevention and modulation of abnormal serum UA
reasons, 2 independent mutations in the uricase gene occurred, levels and associated cardiometabolic complications.
impeding the conversion of UA into a more soluble allantoin like in
other animals [16]. These mutations resulted in higher circulatory
2. Physiology of UA
serum UA levels, predisposing humanity to hyperuricemia and
associated complications. The situation worsened when modern
UA is a natural antioxidant that accounts for approximately 60%
humans adopted “risky” health practices in a bid to modify their
of the total plasma antioxidant activity in the body. It is an organic
lifestyle and improve their environment. The influences and drives
compound comprising carbon, nitrogen, oxygen, and hydrogen
of urbanization, modernization, globalization, and technological
[35] (Fig. 1) and is distributed in the extracellular fluid compart-
advancement have altered resources, environment, and behavior
ment as monosodium urate, which is the final product of purine
on a global scale [17].
metabolism in humans [36]. Diets rich in purines and sugars
These global changes have negatively impacted humanity’s
provide the hepatic precursors for the synthesis of UA and account
traditional dietary habits, resulting in a radical shift from
for approximately one-third of the total body UA pool. Such diets
traditional low-fat diets rich in fiber, fruits, vegetables, complex
carbohydrates, whole grains, legumes, and nuts to Western diets
characterized by high purine, fat, sugar sweetener, fructose, other
caloric sweetener, and refined sugar intake as well as low fruit,
vegetable, and whole grain intake [18–21]. Furthermore, modern
lifestyles are characterized by excessive alcohol intake and reduced
activity. The roles of these modern dietary habits in perturbed
serum UA levels have been documented extensively [12,17].
Interestingly, modern lifestyle habits, particularly nutritional
habits, affect not only the onset, progression, and complications
of perturbed serum UA levels, but also the risks of other chronic
diseases [22] such as diabetes mellitus, hypertension, dyslipide-
mia, cancer, musculoskeletal, renal, cardiovascular, and immune Fig. 1. Structure of uric acid.
 C.E. Ekpenyong, N. Daniel / PharmaNutrition 3 (2015) 29–45 31

Table 1 oxidase [39] (Fig. 2). This pathway is limited by the absence of
Purine contents of certain foods and beverages.
uricase in humans; uricase is an enzyme that catalyzes the
High-purine foods and beverages conversion of UA into a more soluble compound, allantoin, which is
easily excreted in urine. About 70% of the UA generated daily is

All meats including organ meats and meat extracts
excreted renally, and the remaining 30% is excreted via extra-renal

Seafood
routes including the intestine, skin, hair, and nails [40,41]. UA is a

Yeast and yeast extracts
weak acid (pKa 5.8); at pH <5.75, the un-ionized form is

Vegetables: peas, beans, mushrooms, asparagus, spinach, lentils

Beverages: beer and alcoholic drinks
predominant [42], whereas at pH 7.4, the ionized form circulates.
The maintenance of serum UA levels within the normal
Low-purine foods and beverages physiological range (2–7 mg/dL for men and 2–6.5 mg/dL for
women) depends on dietary purine intake, urate biosynthesis, and

Dairy products: milk, cheese, butter
the rate of urate excretion. Most diets that affect serum UA levels

Eggs
affect either the synthesis or excretory pathways of UA. In healthy

Grains/cereals and products, bread, pasta, cakes

Vegetables, fruits, nuts, except peas, beans, lentils, asparagus, spinach subjects, the body tightly regulates the production, utilization, and

Sugars, sweets, gelatin excretion of UA by controlling the cellular turnover of purine

Beverages: water, juices, carbonated beverages, tea, coffee, cocoa intermediates, filtration, reabsorption, and secretion. Disturbances
of these processes can lead to UA levels that are abnormally low
Ref. [9]. (<2 mg/dL) or abnormally high (>7 mg/dL for men and 6.5 mg/dL
for women), which are termed hypouricemia and hyperuricemia,
include but are not limited to meats, meat products, seafood, respectively. Of note, UA levels may vary within an individual by as
beverages (e.g., beer, spirits, and high fructose- and sucrose- much as 59–119 mmol/L during the course of a day owing to diet
containing beverages) (Table 1). Meanwhile, metabolism of and exercise. Approximately 90–95% of UA filtered at the renal
endogenous nucleic acids accounts for the remaining two-thirds glomeruli is reabsorbed from the proximal renal tubules, whereas
of the total UA pool. The pathophysiology of hyperuricemia active secretion into the distal tubule takes place via an ATPase-
includes UA under-excretion, overproduction, or a combination dependent mechanism [43]. Several urate transporters (e.g.,
thereof [37,38]. The pathway for dietary UA synthesis is catalyzed human urate transporter I [hURA1] and hURAT2) and export
by several enzymes including phosphoribosyl pyrophosphate transporters (e.g., organic anion transporter 1 [OAT1], OAT3, and
(PRPP) synthase, PRPP amidotransferase, PRPP glycinamide OAT4) are responsible for urate reabsorption.
synthase, nucleotides, purine nucleoside phosphorylase (PNP), Importantly, the activities of these transporters are pH
hypoxanthine-guanine phosphoribosyltransferase, and xanthine dependent; at acidic pH, human OAT4, which is responsible

Fig. 2. Pathway of the synthesis of purine nucleotides and UA from purine-rich foods and food products. Purine nucleotides (i.e., GMP, IMP, and AMP) are generated from
purine-rich foods (e.g., meats, organ meats, fish, and some vegetables including spinach and asparagus) through a series of enzymatic reactions; this ultimately results in the
formation of hypoxanthine and xanthine, which are converted to UA by xanthine oxidase. UA is metabolized, and approximately 70% of the excreted portion is excreted renally
[40]. UA: uric acid; NT: nucleotide; AMP: adenosine monophosphate; IMP: inosine monophosphate; XO: xanthine oxidase; PPRP: phosphoribosyl pyrophosphate; PNP:
purine nucleotide phosphorylase; GMP: guanosine monophosphate.
32 C.E. Ekpenyong, N. Daniel / PharmaNutrition 3 (2015) 29–45

Table 2 3.1. Food sources modulating serum UA concentration

Summary of the mechanisms by which diet affects serum UA levels.

Foods Mechanism of action Meta-analyses and reviews of numerous dietary trials conclude
"Synthesis #Synthesis "Excretion #Excretion
serum UA levels can be lowered to near-normal ranges with
#Reabsorption "Reabsorption restricted or moderated consumption of certain diets, particularly
Vegetable and fruits – ++ ++ –
high-purine and high-fat diets, as well as excessive alcohol
Coffee – ++ ++ – consumption. Therefore, dietary modification is frequently rec-
Dairy – – ++ – ommended as the first-line intervention to improve serum UA
Cherries – ++ ++ levels in patients with hyperuricemia and gout [46,47]. Conven-
Vitamin C – – ++
tional dietary recommendations known to modulate serum UA
Urine-alkalinizing – – ++ –
foods levels and decrease the risk of hyperuricemia in healthy individuals
Urine-acidifying – – – ++ include low-fat dairy products, whole grains, vitamin C, coffee,
foods nuts, vegetables, and legumes as well as moderation of the
Meat and meat ++ – – ++
consumption of sugary foods, red meat, sea foods, alcohol, fructose,
products
Alcohol ++ – – ++
and sugar-sweetened beverages [48]. For individuals with
Beer ++ ++ established gout, special dietary recommendations have been
Fructose ++ – – ++ made by different bodies including the American College of
Unsaturated fatty – – ++ Rheumatology (Table 3).
acid
Saturated fatty acid – – – ++
Protein – – ++ 3.1.1. Vegetables, fruits, whole grains, legumes, and nuts
The consumption of vegetables, fruits, and other plant-derived
Electrolytes: foods is inversely correlated with hyperuricemia and gout as well
K+ – – ++ –
as the occurrence of metabolic syndrome clusters [49,50]. The
Ca2+ – – +/ –
Mg2+ – – ++ –
effectiveness of diet as a promoter or modulator of perturbed
Na+ – – + – serum UA levels depends on its composition and consumption
pattern. The recent cross-sectional analysis of Guasch-Ferre et al.
++: Persuasive evidence, typically from clinical trials.
+: Suggestive evidence, typically from observational studies and clinical trials. [50] shows that after a baseline dietary induction of hyperuricemia
+/: Indicates limited in equivocal evidence. (with red meat, fish, sea foods, and wine), adherence to a typical
Mediterranean diet, which is characterized by high intake of fruits,
vegetables, legumes, olive oil, nuts, and whole grains as well as
for the inward-directed UA transport (i.e., reabsorption), is moderate intake of wine, dairy products, poultry, creams, and
activated, whereas at alkaline pH, UA hydroxyl (UA/OH) pastries, was inversely correlated with the prevalence of hyper-
exchanger, which is responsible for outward-directed UA uricemia; the correlation was stronger among individuals with
transport (i.e., excretion), is activated [44]. Diet can alter serum higher adherence to the Mediterranean diet than among individu-
UA levels by either enhancing or inhibiting UA synthesis or als with lower adherence. These associations were independent of
competitively inhibiting/enhancing renal reabsorption/excretion. other covariates. In another large population study, Ryu et al. [51]
In addition, diet-induced alterations of pH can enhance UA found that hyperuricemic subjects reported poorer diet quality
reabsorption or excretion (Table 2). than controls, including higher alcohol intake as well as lower
vegetable and diary product intake. The diet of the great apes,
3. Food sources affecting serum UA concentration which mainly comprises fruits and vegetables with only small
amounts of animal protein, may at least in part explain why they
Diet modification is an important and early intervention for have lower serum UA levels from 1.5–3.0 mg/dL (89–117 mmol/L)
modifying risk factors for cardiovascular diseases [45], including than the general human population of the United States.
hyperuricemia and gout. Indeed, dietary intervention remains the The traditional Mediterranean diet, Okinawan diet, Dietary
only non-pharmacological approach that can be used to initiate Approach to Stop Hypertension (DASH) diet, and a dietary portfolio
long-term prevention and control as well as an adjuvant in the of cholesterol-lowering foods have similar characteristics in terms
management of hyperuricemia and gout. Dietary manipulation is a of reducing the risk of hyperuricemia, which is central to the
plausible approach for reducing UA production and/or enhancing development of other chronic diseases [50]. The inverse associa-
UA excretion. tion between the consumption of these foods and serum UA levels

Table 3
Specific dietary recommendations for gout patients based on American College of Rheumatology Guidelines for Gout Management.

Avoid Limit Encourage

Purine-rich foods including organ meats (e.g.,
Serving sizes of beef, lamb, and pork
Low-fat or non-fat dairy products [B]
kidneys) and sweet breads [B]
Seafood with high purine content (e.g., sardines and
Vegetables [C]

Soft drinks, other beverages, and foods containing shellfish) [B]
high fructose corn [C]
Servings of naturally sweet fruit juices

Alcohol overuse (>2 units/day) in all gout patients
Table sugar and sweetened beverages
[B]
Table salt [C]

Any alcohol use in gout patients during periods of

Alcohol (particularly beer but also wine and spirits)
frequent gout attacks or advanced gout under poor
in all patients [B]
control [C]

Evidence grades for recommendations [185].

[A]: Supported by multiple randomized clinical trials or meta-analyses.
[B]: Derived from a single randomized trial or non-randomized studies.
[C]: Consensus opinion of expert case studies or standard of cure.
 C.E. Ekpenyong, N. Daniel / PharmaNutrition 3 (2015) 29–45 33

Table 4
Main groups of flavonoids and food sources.

Group Compound Food sources

Apigenin
Apple seeds

Chrysin
Berries

Kaempferol
Broccoli

Luteolin
Celery

Myricetin
Fruit peels

Rutin
Cranberries

Sibelin
Grapes

Quercetin
Lettuce

Olives
Flavones
Onions

Parsley

Citrus fruit

Citrus peel

Fisetin

Hesperetin

Naringin

Naringenin

Taxifolin

Flavanones

Catechin
Red wine

Epicatechin
Tea

Epigallocatechin

Flavanols

Cyanidin
Berries

Delphinidin
Cherries

Malvidin
Grapes

Pelargonidin
Raspberries

Peonidin
Red grapes

Petunidin
Red wine

Strawberries

Tea

Fruit peels

Anthocyanins

Ref. [53].

is largely attributable to their high levels of polyphenol com- in the purine metabolic pathway according to the following
pounds, vitamins, minerals, and dietary fibers [52]. Phenolic reactions:
compounds including anthocyanins, flavols, flavones, flavanol,
Xanthine + 2O2 H2O ! UA + 2O2 + H+ (i)
flavonones, and isoflavones are widespread in vegetables, fruits,
grains, bark, roots, stem, flowers, teas, and wine (Table 4); they are
15-carbon compounds comprising 2 phenol rings connected by a
Xanthine + O2 + H2O ! UA + H2O2 (ii)
3-carbon unit. They contribute to many physical (e.g., flavor,
astringency, odor, and color), biological, and pharmacological This reaction, particularly phase (ii) reoxidation, generates
properties including the oxidative stability of plants, fruits, and superoxide radicals that initiate oxidative stress, leading to
vegetables. Indeed, chronic consumption of diets rich in plants hyperuricemia [53]. Flavonoids block these reactions and by
polyphenols helps reduce the development of several cardiome- competitively binding to the specific active site of xanthine
tabolic disorders including hyperuricemia and gout. Empirical oxidase, altering its stereochemistry and hence its biochemical
evidence indicates these compounds exert their anti-hyperurice- effect; this consequently blocks the generation of superoxide
mic effect via their antioxidant/radical-scavenging activities and radicals [54]. This inhibitory action is enhanced by the presence
interactions with enzymes involved in UA synthesis (Fig. 3), of olefins at C2 and C3, which maintain the planar structure of
particularly the xanthine oxidase system. Xanthine oxidase flavonoids, hydroxyl moieties at C7 and C5, and carbonyl group
catalyzes the hydroxylation of hypoxanthine to xanthine and UA at C4 in the flavonoid structure [54]. Besides the indirect
34 C.E. Ekpenyong, N. Daniel / PharmaNutrition 3 (2015) 29–45

Diet high in polyphenols

and low in purine

• Inhibion of xanthine • Anoxidant acvity

B A
oxidase • Insulin sensivity
• UA synthesis • Insulin concentraon
• UA/OH− exchanger acvity
• UA excreon
• Serum UA level

Fig. 3. A: Diets high in polyphenols enhance insulin sensitivity and reduce insulin levels by scavenging superoxide radicals via their antioxidant effects. Improved insulin
sensitivity activates uric acid/hydroxyl (UA/OH) exchanger, which increases UA excretion. B: Polyphenols can also inhibit xanthine oxidase activity, decrease UA synthesis, and
subsequently decrease serum UA levels.

antioxidant effect following the inhibition of xanthine oxidase, Several mechanisms by which coffee lowers serum UA levels
flavonoids also scavenge free radicals, making them more stable have been postulated. Accordingly, Kela et al. [68] demonstrated
and less active. During this process, flavonoids themselves the competitive inhibitory effect of caffeine (1,3,7-trimethylxan-
become oxidized as shown in the following reaction: flavonoid thine), a methyl-xanthine, on xanthine oxidase in rats. Other
(OH) + R > flavonoid (O) + RH (1), where R is a free radical and mechanisms include increased insulin sensitivity and decreased
O is an oxygen free radical [53,55]. In addition, dietary fibers insulin concentrations [69,70].
present in vegetables, fruits, and grains may also contribute to
the inverse association between the consumption of these foods 3.1.3. Dairy foods
and serum UA levels by inhibiting the digestion of dietary RNA Dairy foods such as milk, yogurt, and cheese are good sources of
and/or absorption of the hydrolyzed compounds. These actions high-quality bioactive proteins and peptides; they can help protein
suppress the elevation of serum UA levels induced by dietary requirements and provide many other nutrients important for
RNA [56–58]. health owing to their varying and complex bioactive constituents.
The rich electrolyte and mineral constituents of many fruits and Besides protein, dairy also contains lactose, fat, and several
vegetables, including potassium and magnesium citrate, contrib- hundreds of other constituents including vitamin D, orotic acid,
ute to the anti-hyperuricemic effects of vegetables and fruits. flavor compounds, and electrolytes (e.g., Ca2+, Mg2+, and K+).
Potassium-rich foods, namely vegetables and fruits, usually Approximately 80% of the protein in milk is casein, while 20% is
contain large amounts of citrate [59]. The ingestion of K+ citrate whey based [47].
is inversely associated with serum UA levels; this association is Several observational studies and clinical trials highlight the
possible only when magnesium is within physiological concen- significant relationship of dairy and dairy product intake,
trations, because K+ cannot be absorbed efficiently [60]. Thus, the particularly low-fat dairy products, with hyperuricemia and gout
presence of magnesium and potassium in most vegetables [22,32,71–74]. Dairy consumption is consistently found to be
synergistically promote normouricemia. K+ citrate is a known inversely associated with serum UA levels [22]. Both short- and
urine-alkalinizing agent, causing a uricosuric effect. Accordingly, long-term intervention studies demonstrate high intake of milk
K+ citrate has been successfully used to eliminate urate stones [61]. protein or skim milk decreases serum UA concentrations [47,72]. In
addition, evidence suggests continuous consumption of a dairy-
3.1.2. Caffeinated and decaffeinated coffee free diet may be associated with increased serum UA concen-
Several prospective epidemiological studies concordantly trations [72,75]. Schmidt et al. [76] performed a cross-sectional
suggest long-term coffee consumption is associated with lower analysis evaluating the effect of different dietary compositions on
risks of hyperuricemia and gout in both sexes. Although this serum UA levels in 670 men and 1023 women, and found that
association was found for both caffeinated and decaffeinated vegans (i.e., diets containing no animal products) had the highest
coffee, it was stronger caffeinated coffee. This suggests that besides serum UA concentrations among all dietary groups; this finding is
caffeine, other components of coffee may contribute synergisti- partly attributable to the low dairy content in vegan diets, which is
cally to the observed inverse association between coffee intake and also associated with low calcium intake. Another study by Leonen
risk of gout. Besides caffeine, coffee also contains substantial et al. [71] shows that lower intake of bread and milk products is
amounts of polyphenols; a cup of coffee usually contains associated with increased serum UA levels in women.
approximately 100 mg polyphenols [62–64]. Previous research indicates dairy and dairy products exert their
Two cross-sectional studies in Japanese men [65] and American anti-hyperuricemic effects by increasing urinary excretion of UA
adults [66] show a significant inverse association between coffee (i.e., uricosuria) most likely because of their high protein content.
consumption and serum UA levels. In addition, in a large Dietary protein is associated with increased urinary UA excretion.
prospective study in women, Choi and Curban [66] show that The high protein content of diary is posited to increase the
the risk of incident gout decreases with increasing coffee intake; excretion of free amino acids, which are actively reabsorbed;
the risk is 22% lower with 1–3 cups/day and 57% lower with furthermore, some amino acids are thought to compete more
>4 cups/day compared to the risk in individuals who consume favorably than UA for reabsorption [77]. Therefore, the quantity of
0 cups/day. A 12-year prospective study shows similar results: the dairy and hence protein as well as purine and fat content are
risk of gout was 40% lower with coffee intake of 4–5 cups/day and factors that could affect the anti-hyperuricemic activity of dairy
59% lower with 6 cups/day compared to 0 cups/day. Modest and dairy products. For example, 30 g dairy protein did not
inverse associations were observed with regard to decaffeinated significantly alter plasma UA levels in the study of Ghadirian et al.
coffee consumption. These associations are independent of other [75]. Meanwhile, in a short-term randomized controlled crossover
confounding factors [67]. study, Dalbeth et al. [74] found that 80 g of various dairy protein
 C.E. Ekpenyong, N. Daniel / PharmaNutrition 3 (2015) 29–45 35

significantly decreased plasma UA level while significantly Jacob et al. [86] investigated the effect of cherry juice
increasing urinary excretion of UA, indicating a dose-dependent consumption on serum UA levels in healthy women aged
effect. This finding corroborates previous studies demonstrating 22–44 years; the participants who consumed 2 servings (280 g)
that increased dietary protein content increases uricosuric activity of cherries after an overnight fast had significantly decreased
[78,79]. Besides the quantity of protein consumed, modulatory plasma UA levels from 214 to 188 mmol/L 5 h post-dose, while
effect of a protein-rich diet on serum UA concentration may also be urinary UA levels increased significantly from 202  13 to
confounded by dietary purine content. High-protein diets rich in 350  33 mmol/mmol creatinine after 3 h. These findings suggest
purines (e.g., soy protein, meat, and seafood) may provide a the decrease in plasma UA concentration was partly due to
concomitant purine load, increasing uricogenesis and consequent- increased excretion. In addition, biomarkers of inflammatory
ly leading to hyperuricemia regardless of the uricosuric effect of response, such as C-reactive protein and nitric oxide, decreased,
the protein [79]. One study [79] assessed the effects of equal intake indicating the anti-inflammatory activity of cherries [88],
of 3 different proteins (i.e., casein, lactalbumin, and soybean supporting their use in herbal medicines to relieve arthritic joint
isolate) on serum UA concentration and urinary UA excretion in pain [83]. Similar results were obtained in a parallel study by
10 healthy subjects. Serum UA concentration decreased signifi- Zhang et al. [89], who assessed the effectiveness of cherry juice in
cantly 3 h after the ingestion of casein and lactalbumin but alleviating recurrent attacks of gout in 633 patients. Cherry juice
increased in the soy protein group. In all cases, urinary excretion of consumption over a 2-day period was independently associated
UA increased. with a 35% lower risk of gout attacks compared with no intake.
The decrease in serum UA concentration in the dairy protein The addition of allopurinol further decreased the risk to 75%
groups and increase in the soy protein group can be explained by lower than that without intake; this provides evidence of an
the fact that dairy proteins have low purine content and may additive effect that could be useful in managing recalcitrant cases
exert their uricosuric effect without providing the concomitant of gout but could also incur a risk of hypouricemia in cases of
purine load contained in soy protein. In addition, the intake of a unnecessary co-administration.
large amount of low-fat milk acutely decreases UA concentration Schlesinger [90] assessed the effects of cherry juice consump-
[74], whereas full-fat dairy has no effect [22]. Also, enrichment of tion on the frequency (i.e., progression) of gout attacks and the
dairy and dairy products with certain dairy fractions including intensity of arthritic pain and found that the consumption of
glycomacropeptide (GMP) and G600 milk fat extract [47] provide cherry juice concentrate significantly reduced the frequency of
a significant anti-inflammatory effect in experimental models of acute gout attacks; approximately 92% of patients achieved a  50%
gout [74]. In one study, enrichment of skim milk powder with reduction in acute gout episodes.
GMP and G600 was associated with significant long-term Howatson et al. [91] performed a placebo-controlled study of
reductions in gout pain, improved flare frequency, and other 25 marathon runners to assess the efficacy of tart cherry juice in
endpoints [80]. As mentioned above, dairy and dairy products aiding recovery and reducing muscle damage, inflammation, and
also contain other bioactive substances including electrolytes oxidative stress. They found serum UA levels were higher in the
including Ca2+, Mg2+, phosphorus, K+, and vitamin D. These placebo group at the immediate post race period, and at 24 h post-
substances conceivably confer a combined protective effect race. This result suggests cherry juice has an ameliorative effect on
against hyperuricemia, gout, and other associated complications. exercise-induced elevation of serum UA concentration and
For example, intravenous calcium chloride increased UA excre- associated complications. Concordantly, an animal study by
tion in a short-term study of patients with idiopathic urolithiasis Haidari et al. [85] revealed that decreased plasma UA concentra-
[80]. Moreover, in a cohort study of men and women aged tion in the cherry-fed group was associated with the inhibition of
20 years or older, dietary Ca2+ was inversely correlated with hepatic activities of xanthine oxidase and xanthine dehydroge-
serum UA concentration [76]. Similarly, orotic acid present in milk nase; this suggests cherries may possess the capacity to reduce UA
may reduce serum UA concentration by promoting renal UA production, which is a plausible mechanism for its hypouricemic
excretion [81,82]. It should be noted that the association between effect. Jacob et al. [86] report that decreased serum UA and
Ca2+ intake and serum UA concentration is inconsistent in the creatinine levels as well as an increased urinary UA levels following
literature [83] probably because of confounding metabolic and the consumption of cherry juice are biochemical markers of
biochemical covariates. As mentioned above, K+ intake is increased glomerular filtration rate and/or decreased tubular
inversely correlated with serum UA concentration, especially reabsorption; this suggests increased urinary UA excretion might
when the concentration of Mg2+ is within the normal physiologi- be another plausible mode of the effect of cherries. However,
cal range. Therefore, it can be concluded that decreasing the which of these 2 hypouricemic mechanisms is more likely the
purine and fat content while maintaining a moderate protein responsible one requires further research. Another animal study
content in dairy and dairy products boosts their anti-hyper- from China reaffirms the importance of cherries in reducing
uricemic effect in humans. arthritis-associated inflammation in rats; besides the increased
antioxidant effect, that study also shows cherries decreased
3.1.4. Cherries and cherry products inflammatory markers including tumor necrosis factor-alpha
The consumption of cherries and cherry products has long been and prostaglandin E2 [92], further confirming the anti-inflamma-
reported to provide unique activities against gout and inflamma- tory effects of cherries and cherry products.
tion [84] owing to their ability to reduce serum UA level and Finally, substantial evidence indicates cherries and cherry
suppress inflammatory changes in affected individuals. These products can modulate serum UA levels in hyperuricemic and
activities are partly attributable to their ability to inhibit UA normouricemic individuals; they are postulated to enhance renal
synthesis [85] and/or enhance UA excretion (i.e., the uricosuric excretion of UA (i.e., uricosuric effect) and have xanthine oxidase
effect) [86] as well as their antioxidant-boosting properties owing and xanthine dehydrogenase inhibitory effects.
to their high polyphenol contents. Cherries, grapes, apples, pears,
and berries contain 200–300 mg polyphenols per 100 g fresh 3.1.5. Vitamin C
weight [61]. Accordingly, the consumption of approximately 225 g Vitamin C is an essential micronutrient that functions as a non-
cherries or drinking an equivalent amount of cherry juice is enzymatic water-soluble antioxidant in numerous chemical
reported to prevent attacks of gout irrespective of the cultivar or reactions in plasma and tissues [93]. Higher vitamin C intake is
taste [87]. significantly associated with lower incidences of cardiovascular
36 C.E. Ekpenyong, N. Daniel / PharmaNutrition 3 (2015) 29–45

risk factors including hyperuricemia and gout in several epidemi- meats, meat products, organ meats, seafood, and mushrooms
ological studies [93–96]. (Table 1). High intake of these foods and food products are
These inverse associations are independent of the administered positively correlated with higher serum UA levels and gout
doses, administration duration, study population size, and dietary [32,45,105] because of their high purine and nucleic acid contents.
and other risk factors for hyperuricemia [93–95]. For example, a Purine nucleic acid intake strongly influences blood UA level.
recent prospective study that followed a cohort of 46,994 men for Intake of an oral purine load by humans can increase serum UA
20 years found that higher vitamin C intake (1500 mg/day) was level by 59–119 mmol/L (1.0–2.0 mg/dL) within 24 h, whereas an
associated with a 45% lower risk of gout [94]. One study found that equicaloric purine-free diet will take 7–10 days to decrease serum
vitamin C supplementation (500 mg/day) for 2 months in UA level by the same amount [33,77,106–108].
184 participants reduced serum UA levels by 0.5 mg/dL [93]. Lyu Several studies confirm the direct relationship between the
et al. [95] report similar observation in a retrospective Taiwanese consumption of a purine-rich diet and incident hyperuricemia and
case-control study that involved 182 participants (91 gout cases gout (Table 5). One such study is the Dutch Nutritional Surveillance
and 91 controls). Furthermore, these findings are consistent with Study, which found that higher meat and fish consumption was
the observations of Gao et al. [96] in a study of 1387 men. associated with increased serum UA levels [109]. Furthermore,
The potential mechanism(s) by which vitamin C reduces serum beef and haddock consumption increased serum UA levels 2–4 h
UA levels may include increased glomerular filtration rate and/or postprandially. In the Health Professionals Follow-up Study of
increased urinary excretion (i.e., uricosuric effect) [93,96–100]. The 47,150 men aged 40–75 years, an additional daily serving of meat
uricosuric effect of vitamin C may be due to competition for renal and weekly serving of seafood were associated with 21% and 7%,
reabsorption for UA via an ion exchange transport system in the respectively, increased risks of gout, with a higher relative risk in
kidneys [94,98]. Emerging evidence suggests vitamin C may exert patients with gout than normouricemic individuals [32]. The US
its uricosuric effect via the cis-inhibition of UA transporter 1, National Health and Nutrition Examination Survey III of
sodium dependent anion co-transporter, or both in the proximal 14,809 yielded a consistent result [22]. The etiological role of
tubules [94]. purine-rich foods and food products include increased UA
production as well as decreased renal excretion and/or increased
3.1.6. Urine-alkalinizing/acidifying foods renal reabsorption (Table 2). The hyperuricemic, gout, and
Normal metabolic activities in the body require a slightly uricosuric potentials of purine-rich foods may depend on the
alkaline pH of 7.35–7.45 (mean: 7.4) [101]. Even a slight deviation predominant purine nucleoside, nucleotide, and bases as well as
from these values may lead to serious metabolic derangements the individual’s baseline uricemic status [108,109]. Foods contain-
including abnormal serum UA levels due to alteration in renal ing more adenine evidently have a greater effect on serum UA
regulatory mechanisms. The reabsorption mechanism of UA and levels than food containing mainly guanine [78]; similar effects are
hence hyperuricemia is more active in acid-prone environments, reported for foods containing more RNA than DNA [106], and more
whereas renal excretion is higher in alkaline environments [102]. ribonucleotides than nucleic acids [22,110]. Other studies [109,110]
Urine alkalinization aids solubility and increases the transportable show oral hypoxanthine, adenosine monophosphate (AMP),
proportion of UA and thus excretion. In fact, at a physiological pH of guanosine monophosphate (GMP), inosine monophosphate
7.4, approximately 98% of UA is solubilized [10]. The high solubility
of UA in an alkaline urine environment is beneficial as it reduces
the risk of UA lithiasis. Conversely, an unusually acid urinary Table 5
Associations of foods with serum UA concentrations and urinary UA excretion.
environment (pH <5.5, which is below the dissociation constant of
UA) is common in patients with UA lithiasis. The relationships of Foods/food products Serum UA Evidence Urinary UA Evidence
urinary and blood pH with serum and urinary UA levels have been concentration excretion
studied extensively [30,43,103]. In healthy individuals, urinary pH Vegetables and fruits Inverse ++ Direct ++
is determined by acid/alkaline generation from food metabolism Caffeinated and non- Inverse ++ Direct ++
caffeinated coffee
[103], suggesting urine with the desired pH could be generated by
Dairy and dairy Inverse ++ Direct ++
eating a specific diet [30,102]. products
Manipulating urinary pH by diet is a plausible effective dietary Cherries and cherry Inverse ++ Direct ++
approach/intervention for the prevention of abnormal serum UA products
levels and associated complications. This idea is supported by Vitamin C Inverse ++ Direct ++
Alkalinizing foods Inverse ++ Direct ++
Kanbara et al. [102], who used an alkaline diet to increase the Fibers Inverse ++
transportable proportion of UA and hence its excretion even in Protein Inverse ++ Direct ++
low-purine foods. The molecular basis of the pH-dependent renal Meats and meat Direct ++ Inverse ++
UA transport system on the renal reabsorption/excretion of UA has products
Acidifying foods Direct ++ Inverse ++
been postulated. Hagos et al. [104] report that human organic
Seafood Direct ++ Inverse ++
anion transporter 4, which is responsible for inward-directed UA Fructose and fructose Direct ++ Inverse ++
transport, is activated in acidic environments, whereas UA/OH corn syrup
exchanger, which is responsible for outward-directed UA trans- Fat Direct ++ Inverse +
port, is activated in alkaline environments [43]. Protein-rich vegetables Inverse + Direct +
Wines Inverse + Direct +
Beans and peas Inverse + Direct +
3.2. Foods that increase serum UA levels Fish oil and plant oil Uncertain + Uncertain +

3.2.1. Meat, meat products, and seafood Electrolytes

K+ and Mg2+ Inverse ++ Direct ++
Approximately one-third of the total body UA is derived from
Ca2+ Uncertain  
dietary purines; this fraction constitutes the modifiable portion of Na+
the body’s UA pool and is responsible for the differences in serum
++: Persuasive evidence, typically from clinical trials.
UA levels among normal individuals. Therefore, dietary purine +: Suggestive evidence, typically from observational studies and clinical trials.
intake is a significant contributor to serum UA levels. There is a : Limited or equivocal evidence.
growing list of purine-rich foods and food products, including UA: Uric acid.
 C.E. Ekpenyong, N. Daniel / PharmaNutrition 3 (2015) 29–45 37

(IMP), and adenine produce greater hyperuricemic effects, while the consumption of purine-rich vegetables including beans, peas,
xanthine and guanine do not affect serum UA levels. and lentils is not associated with an increased risk of hyperurice-
Hypoxanthine, AMP, GMP, and IMP cause greater hyperuricemic mia or gout because of their low purine content [32,94], with
effects in subjects with gout than hyperuricemic and normour- exception of dry mushrooms and soybeans; furthermore, the
icemic subjects; furthermore, hypoxanthine, GMP, IMP, and purine contents of plant foods including beans, peas, and sprouts is
adenine have greater hyperuricemic effects than xanthine and markedly less than those in meat and fish [72,111].
guanine [110]. Regarding the effects of different purine derivatives
on the urinary uric acid/creatinine ratio, an index of UA clearance, 3.2.2. Beer and spirits
hypoxanthine, AMP, GMP, and adenine increase the urinary uric The associations between alcohol consumption, and hyperuri-
acid/creatinine ratio in controls, and patients with hyperuricemia cemia and gout have been recorded throughout history. In the 5th
and gout. Conversely, adenine increases the urinary UA/creatinine century BCE, Hippocrates affirmed the pathogenic role of excessive
ratio in controls and hyperuricemic patients but not in patients food and alcohol intake in gout and recommended reducing
with gouty arthritis, while xanthine and guanine do not affect alcohol intake as a preventive measure and disease management
urinary UA/creatinine ratio in any group [110]. These differences [112]. In 1713, John Martin described alcohol as the first and remote
may be in part due to differences in the absorption, utilization, and or procatarctic cause of gout [9]. In 1863, Alfred Garrod rhetorically
degradation of purines contained in different foods [32]. Given that affirmed the role of alcohol in the pathogenesis of gout [9,113].
purine nucleotides, nucleosides, and bases are metabolized According to Fam [9], nearly all accounts of gout emphasize the
differently and produce different degrees of uricemia in normal, role of extensive alcohol consumption. To date, several epidemio-
hyperuricemic, and gouty humans and animals [109,110] owing to logical studies have identified alcohol as a trigger of incident
differences in their uricogenic and uricosuric potentials, it is hyperuricemia and gout. Several metabolic studies show that
conceivable that the consumption of different foods containing alcohol loading induces hyperuricemia [114,115]. The consistency
different purine nucleotides, nucleosides, and bases could produce of the positive association of alcohol intake with incident
different uricemic and uricosuric effects under the same physio- hyperuricemia was reaffirmed by Sun et al. [34], who found that
logical conditions. Habitual long-term intake of a purine-rich diet most previously implicated dietary components were negatively
may activate inactive renal tubular genetic defects [9] and associated with hyperuricemia except alcohol. Therefore, serum
metabolic syndrome clusters in some individuals, leading to UA levels may indeed be a sensitive marker of recent alcohol intake
insulin resistance and intense hyperuricemia (Fig. 4). as described previously [116,117]. Several studies show a strong
Unfortunately, the precise identities and quantities of individ- and significant association between alcohol intake and gout
ual purines in most foods remain unknown, and research on the [88,118,119].
effects of cooking on purine content and quality in foods is limited Empirical evidence indicates acute alcohol excess may cause
even as most purine-rich foods are eaten cooked. There are temporary lactic acidemia, because lactic acid is an antiuricosuric
conflicting hypotheses regarding the changes in purine content agent that increases proximal tubular urate reabsorption and
following the boiling and broiling of purine-rich foods. Boiling reduces renal urate excretion, leading to hyperuricemia
purine-rich foods is thought to break down purines into nucleic [114,116,120,121]. Meanwhile, chronic alcohol intake may stimu-
acids, thereby increasing free purines and enhancing absorption late purine production by increasing the breakdown of ATP to AMP
and bioavailability. One animal study shows feeding rats cooked via the conversion of acetate to acetyl coenzyme A in the
food improves absorption and excretion of purine-related com- metabolism of alcohol. Ethanol is posited to increase UA
pounds. Conversely, cooking food with water releases some of the synthesis by enhancing the turnover of adenine nucleotides [122]
purines into the cooking water, meaning they are never ingested (Figs. 5 and 6).
[108]. In addition to the inconclusive and inconsistent nature of Moderate and heavy but not mild alcohol consumption
these hypotheses, most of these studies are animal based, making significantly increases serum UA levels. However, the increase in
the results not completely applicable to humans. Therefore, more serum UA is correlated with absolute daily alcohol intake [9]. In the
empirical data on the effects of cooking on the bioavailability of Health Professionals Follow-up Study, Choi et al. [32] assessed the
purines and purine-related compounds are required. In addition, effects of different types of alcohol on serum UA levels in

Habitual intake of diets high in

C purines but low in polyphenols

Acvaon of inacve renal

tubular genec defect

• Nucleoside • Insulin resistance

• Insulin concentraon
A • UA synthesis B
• hOAT4 acvity
• Metabolic • Acidity
syndrome
• UA reabsorpon
• Serum UA • UA excreon

Fig. 4. A: Diets high in purine can increase UA synthesis, thus increasing serum UA levels because of the effect of purine nucleotide, nucleosides, or bases. B: This scenario can
also predispose an individual to insulin resistance and increase serum insulin levels, which could precipitate metabolic syndrome and exacerbate the increase in serum UA.
The high protein content of purine-rich meats and meat products can generate substantial fixed acids, leading to acidemia, the activation of human organic acid Transporter 4
(hoAT4), inward-directed UA transport, and increased serum UA. C: Habitual intake of foods high in purines but low in polyphenols can activate inactive renal tubular genetic
defects that could lead to increased serum UA levels.
38 C.E. Ekpenyong, N. Daniel / PharmaNutrition 3 (2015) 29–45

A B C
Glucose Alcohol Fructose

Pyruvate

NADH Fructose 6 (P)

NAD+
Lactate
Acetate
ATP

ADP AMP ADP

Fructose 1, 6-D (P)
Renal UA excreon Acetyl CoA Adenine

Lactate
CO2 + H2O UA synthesis
Renal UA excreon

Serum UA concentraon

Fig. 5. A: Glycolysis results in pyruvate production via anaerobic metabolism. Pyruvate is normally not metabolized to lactate but is under conditions in which the ratio of
reduced nicotinamide adenine dinucleotide (NADH) to oxidized nicotinamide adenine dinucleotide (NAD+) is increased, such as after heavy consumption of alcohol. Pyruvate
is reduced to lactate, which subsequently accumulates. Accumulated lactate impedes renal UA excretion. B: Besides the abovementioned effect, ethanol metabolism
stimulates purine production by increasing the breakdown of ATP to AMP via the conversion of acetate to acetyl coenzyme A. The metabolisms of purine base increase UA
synthesis, increasing serum UA levels. C: Like ethanol, fructose metabolism produces AMP and subsequently increases UA synthesis; it also causes the accumulation of lactate,
consequently reducing renal UA excretion and subsequently increasing serum UA levels.

11,560 American men and women; they found that high beer and to a greater hyperuricemic effect than spirits [115,123]. Taking into
spirit intake but not moderate wine intake were independently account the direct effect of oxidative stress on serum UA levels and
associated with a risk of gout, with beer conferring a greater risk high contents of polyphenols and other antioxidants in wine, the
than spirits. Unlike spirits and most other forms of alcohol, several inverse relationship between wine consumption and serum UA
studies show beer contains higher levels of readily absorbable levels is plausibly a direct effect of the antioxidants in wine, which
purine guanosine than other purine derivatives; furthermore, could mitigate the effect of oxidative stress-induced hyperurice-
ingestion of guanosine can further increase UA synthesis, leading mia in subjects who consumed alcohol [124,125].

A B
Fructose Ethanol
Alcohol dehydrogenase

Schiff base Acetaldehyde

Posive
energy O+
Lipogenesis
balance Heyns De novo
product ROS Obesity
Dyslipidemia
Insulin
Renal Na+
resistance
reabsorpon
Obesity &
dyslipidemia hOAT4 acvity
Ammoniagenesis HBP
UA/OH exchanger

Met-S Acidity Inhibit NO synthase

Intrarenal rennin
End. NO bioavailability
UA excreon
UA reabsorpon

SUA

Fig. 6. A: The process by which fructose and ethanol generate reactive oxygen species (ROS). Fructose first forms an intermediate Schiff base with E-amino group of lysine.
This is followed by a spontaneous hydrogenation, forming an irreversible Heyns product (i.e., hydroxyamide linkage or fructose adduct). This process, termed the Maillard
reaction, generates superoxide radicals that can lead to peroxidation, insulin resistance, impaired renal urate excretion, and hyperuricemia if not quelled by adequate
antioxidants. High fructose or sucrose consumption can cause a positive energy imbalance and stimulate long-chain fatty acid synthesis, leading to hypertriglyceridemia,
obesity, insulin resistance, and increased serum UA levels [144,155,184]. B: Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase, which then participates in the
same Maillard reaction to form acetaldehyde adducts and ROS, which leads to peroxidation [183].
 C.E. Ekpenyong, N. Daniel / PharmaNutrition 3 (2015) 29–45 39

Neogi et al. [126] performed a prospective internet-based case- physiological action on the renal tubules, including reducing
crossover study assessing the effects of quantity and type of alcohol sodium and UA excretion [142] (Fig. 6).
consumed on the risk of recurrent gout; they found episodic alcohol Epidemiological evidence indicates fluctuating trends in the
intake regardless of the type of alcohol was associated with an consumption of fructose-containing beverages in many countries
increased risk of recurrent gout. A similar study in regular and [143–146]. These varying trends may in part be due to the
irregular alcohol drinkers by Bartimaeus and Eno-Eno [127] found a discrepant results obtained from studies performed in different
significant increase in serum UA level in both groups, indicating a parts of the world on the association between fructose-containing
direct association between alcohol consumption and serum UA beverage consumption and adverse health outcomes. It remains
levels. In other words, alcohol directly affects serum UA levels. controversial whether fructose-containing beverages cause hyper-
Therefore, patients with gouty arthritis who consume any alcohol uricemia or increase the risk and complications of hyperuricemia.
may have a higher risk of precipitating and prolonging gouty attacks. Many studies such as those of Johnson et al. [145], MacDonald
Several mechanisms are implicated in the pathogenesis of alcohol- [147], Emmerson [148], and Fox [149] indicate the association
induced hyperuricemia, including both increased production [12] between fructose-containing beverage consumption and an acute
and decreased excretion of UA [121]. Biochemical evidence indicates increase in serum UA levels is strong. Meanwhile, other authors
chronic alcohol metabolism produces net ATP degradation to AMP such as Crapo [150], Huttenen [151], Curari and Pruitt [152], Osei
and subsequently to UA (Fig. 5). and Bosseti [153], Anderson [154], Koh et al. [155], Grigoresco et al.
[156], and Sun et al. [34] report no or marginal associations. This
3.2.3. Fructose and fructose-sweetened beverages controversy has created confusion and alarm among the general
The consumption of fructose or fructose-sweetened bever- public. Although previously unexplained [157], emerging evidence
ages including high fructose corn syrup (HFCS) is strongly suggests the effects of several covariates could have influenced the
correlated with higher serum UA levels. Fructose has high purine results obtained by some investigators, often leading to an inability
content, and rapidly elevates serum UA levels when consumed in to distinguish between an association and causality [139]. For
large amounts. In fact, daily consumption of several brands of example, differences in study subjects, methodology, design,
fructose-sweetened soft drinks increased the risk of hyperurice- categorization of fructose intake groups, and hyperuricemia
mia 1.82 fold in all populations [128]. In a recent cross-sectional criteria [34] have been observed among studies. Some studies
study of 6705 men and women aged 18–70 years using data from used older participants [158], younger participants [159,160], and
the Mexican Health Workers Cohort Study, Leon et al. [129] mixed populations (i.e., both young and old) [129]. The confound-
found that the consumption of sweetened beverages was ing effect of age-related deterioration in renal function and hence
independently associated with an increased risk of hyperurice- UA excretion could be responsible for the disparity in serum UA
mia in Mexican adults. The study shows that compared to men levels among studies. Furthermore, differences in cut-offs for
who consumed 0 sweetened beverages per day, men who determining hyperuricemia may have affected the statistical
consumed 0.5–1 and 3 sweetened beverages per day had significance of the results.
1.59- and 2.29-fold higher risks of hyperuricemia, respectively. Some studies analyzed the effects of mixed sugar diets or pure
Meanwhile, compared to women who consumed 0 sweetened glucose versus fructose diets. However, a lack of fructose content
beverages per day, women who consumed >1.0 and data for many food items used makes comparison among studies
<3.0 sweetened beverages per day had 1.33- and 1.35-fold difficult. In addition, the effect of individual tolerance cannot be
higher risks of developing hyperuricemia, respectively. In a excluded [161]. Rippe et al. [144] state that more randomized
national representative sample of 4867 American adolescents, control trials at normal levels of consumption using commonly
higher consumption of sugar-sweetened beverages was associ- consumed sugars are necessary to resolve these issues. This is
ated with higher serum UA levels and systolic blood pressure pertinent, because there could be a threshold for fructose-
[130]. Similarly, Stanhope et al. [131] found that a high-fructose mediated ATP depletion/AMP production that is thought to
diet specifically induces dyslipidemia, insulin resistance, and increase UA levels [157]; accordingly, neither HFCS nor sucrose
increased visceral adiposity. These findings are consistent with is commonly consumed by humans in isolation but rather in
many others in the literature [132,133]. Fructose consumption combination with other substances [144].
increased approximately 2000% over 30 years since its introduc-
tion in 1967 [134]. This may partly explain the dramatic increase 3.3. Effects of macronutrients on serum UA levels
in the global incidence of abnormalities involved in metabolic
syndrome, including hyperuricemia, since the introduction of 3.3.1. Complex versus simple carbohydrates
commercially produced HFCS [135]. High intake of refined carbohydrates may increase the risks of
Increased fructose intake is hypothesized to increase serum UA insulin resistance [161–164] and associated complications
levels by increasing ATP degradation to AMP and activating the including hyperuricemia and gout. Furthermore, high intake of
pathway of purine degradation to urate [136,137] – a cascade of refined carbohydrates is associated with increased glycemic load,
processes that begins with fructose phosphorylation [138] (Fig. 5). which is known to increase the risks of obesity, glucose
Other possible mechanisms include the production of reactive intolerance, dyslipidemia, and type 2 diabetes mellitus [38,39]
oxygen species, activation of cellular stress pathways, and and hence insulin resistance and hyperuricemia. However, it is
increased UA synthesis [139] (Fig. 6). Furthermore, fructose noteworthy that in healthy individuals, the uricogenic effects of
reportedly inhibits UA excretion, apparently by competing with simple sugars vary depending on the type of reducing sugar(s)
the access of UA to the transport protein, SLC2A9 [140]. Besides consumed. In various experimental and short-term feeding trials
fructose, substrates such as sorbitol, sucrose, lactate, and in humans, the uricogenic potential of fructose appears to be
methylxanthines [141] increase serum urate levels. In addition, strong and consistent [165–167]; that for glucose may be weak or
the etiological role of high fructose consumption in metabolic absent [165]. Unlike glucose, fructose metabolism in the liver
syndrome clusters including insulin resistance and obesity is generates AMP and subsequently increased UA synthesis [128].
postulated to indirectly increase serum urate levels and the overall Conversely, high plasma glucose levels as in diabetes mellitus
risk of gout. Fructose consumption favors positive energy balance, may be associated with decreased serum UA levels because of the
leading to insulin resistance and obesity [135]. In turn, insulin uricosuric effect of glycosuria [168]. This may at least in part
resistance leads to hyperinsulinemia and intensification of its explain the inconsistent results in the literature with respect to
40 C.E. Ekpenyong, N. Daniel / PharmaNutrition 3 (2015) 29–45

the association between high intake of carbohydrates including 3.3.5. Proportions of macronutrient intake
simple sugars and incident hyperuricemia. On the other hand, Some macronutrients such as simple sugars and fat are
complex carbohydrates, particularly those from vegetables, fruits, obesogens and are hence associated with insulin resistance and
whole grains, legumes, and dairy products, are inversely consequently increase insulin levels; meanwhile, others such as
associated with serum UA levels. proteins and complex carbohydrates are weight modulators and
are associated with increased insulin sensitivity and consequently
3.3.2. High-fat versus low-fat diets decrease insulin levels. Therefore, macronutrient intake with
Some early and recent studies show high-fat diets but not low- greater proportions of proteins and complex carbohydrates may be
fat diets are associated with elevated serum UA levels [169,170]. beneficial in patients with hyperuricemia and gout by lowering
However, this association was stronger with diets containing serum UA levels and decreasing the frequency of gout attacks by
foods high in saturated than those with unsaturated fat. Several ameliorating the pathogenic role of insulin resistance in hyperuri-
meta-analyses and reviews of dietary trials demonstrate the cemia and gout. Accordingly, insulin resistance is a known trigger
substitution of saturated fatty acids with either mono- or of hyperuricemia and gout [175–177].
polyunsaturated fatty acids lowers serum UA levels and other Dessien [175] performed a dietary intervention study of
cardiovascular risk factors [44]. These results suggest the 13 subjects aged 38–62 years with intermittent gout who were
quantities of saturated fat and full-fat dairy should be reduced fed a diet (6690 kJ/day) comprising 40% carbohydrates, 30%
in many dietary intervention strategies aiming to modulate protein, and 30% fat; mean serum UA levels decreased significantly
cardiovascular disease, including diets aiming to lower serum UA by 18%, and monthly gout attack frequency was reduced by 67%.
levels such as the DASH diet plan, portfolio diet, Mediterranean Special characteristics of the above mentioned diet include calorie
diet (high in mono- and polyunsaturated fatty acids), and the low- restriction, replacement of refined carbohydrates with complex
fat Okinawan diet [48,49]. A few other population-based ones and saturated fat with mono- and polyunsaturated fats, and
prospective studies on the effects of varying proportion of high protein intake. The findings of that study are consistent with
monounsaturated and saturated fatty acids in diet show that previous studies showing that a low-energy high-protein diet
more monounsaturated fatty acid than saturated fatty acid improves insulin sensitivity and ameliorates hyperuricemia and
content produces beneficial effects regarding remission of gout, whereas a low-energy high-carbohydrate diet decreases
symptoms in gout patients. The associations of a high-fat diet insulin sensitivity [178] and aggravates hyperuricemia and gout.
with obesity and insulin resistance may underlie the pathogenic Several early studies suggest diets high in fat and low in
effect of high-fat diets [171]. High-fat diets can lead to excessive carbohydrates increase serum UA levels in gout patients whereas
storage of fatty acids in white adipose tissue as well as organs diets high in carbohydrates and low in fat decrease serum UA levels
such as the heart, liver, and skeletal muscles, leading to obesity in the same group of patients [179]. Nevertheless, clinical evidence
and insulin resistance [172]. However, fat quality appears to be far suggests there are no ideal percentages of calories from
more important than quantity. carbohydrates, protein, and fat for all people with hyperuricemia
and gout, similar to that for other cardiovascular risk factors.
Therefore, macronutrient distribution should be individualized on
3.3.3. Fish and plant oils
the basis of assessment of current eating patterns, preferences, and
Fish and plant oils have long been suggested for the treatment
metabolic goals. Thus, personal preferences (e.g., tradition, culture,
of gout [50]. However, while several studies show fish oil dietary
religion, economics, health beliefs, and goals) and metabolic goals
supplementation can be used to alleviate gout symptoms, there is
should be considered when recommending one eating pattern
no evidence showing it has any significant modulatory effect on
over another.
serum UA levels. The hypothesis that fish and plant oils can be used
to treat gout may have been based on anecdotal experience. For
3.4. Effects of electrolytes and mineral on serum UA levels
example, the ameliorative effect of fish oil supplementation on
gout symptoms was first reported by a Chinese physician when he
3.4.1. Potassium and magnesium
experienced symptomatic relief of rheumatoid arthritis after
Observational and clinical trials demonstrate an inverse
consuming vegetable and fish oils. Therefore, fish and plant oils
association between potassium supplementation and serum UA
may merely ameliorate inflammation and hence gout symptoms
levels, whereas urinary potassium is directly associated with
owing to their high levels of eicosapentaenoic and gamma linoleic
serum UA levels. High potassium intake, particularly in the form
acid, respectively.
of potassium bicarbonate or citrate, is associated with reduced
serum UA levels [180]. This is corroborated by several studies
3.3.4. Protein-rich foods and food products showing an inverse association between serum potassium levels
The relationship between high intake of protein-rich foods and and rheumatoid arthritis [181,182]. In the National Health and
food products is well documented. Higher intake of vegetable Nutrition Survey, participants with low plasma potassium levels
protein is associated with a reduction in serum UA levels [78,115], exhibited a higher incidence of rheumatoid arthritis. Rodman
while lower protein intake may be associated with hyperuricemia [183] reports that gout can be triggered by the same agent that
and gout [115]. These observations are corroborated by the studies cause K+ losses, including K+-losing diuretics, fasting, and surgery.
of Jenkin et al. [173] and Choi et al. [38] using data from the Third The mechanism underlying the inverse association between
National Health and Nutritional Examination Survey (1988–1994). potassium intake and serum UA levels may include potassium’s
The mechanism by which high-protein diets decrease serum UA uricosuric activity. Potassium in the form of potassium citrate acts
levels is hypothesized to involve increased urinary UA excretion. as an alkalinizing agent. Alkaline urine activates UA/OH exchang-
Emerging research indicates high-protein diets increase excretion er, which is responsible for the outward transport and hence
of free amino acids, which are actively reabsorbed and could excretion of UA [43]. Interestingly, the uricosuric action of K+ is
compete more favorably than UA for reabsorption. Furthermore, only effective in the setting of adequate plasma levels of
the consumption of protein-rich diets may increase blood and magnesium. Magnesium enhances the absorption of K+ probably
urinary urea concentrations, although evidence for this is weaker by activating the K+ pumping mechanism. Potassium citrate is
and inconclusive. Urea is hypothesized to enhance renal UA preferred in the management of UA lithiasis because it incurs no
excretion [174]. complications associated with sodium alkaline, such as the
 C.E. Ekpenyong, N. Daniel / PharmaNutrition 3 (2015) 29–45 41

precipitation of calcium nephrolithiasis and formation of mono-

Layperson’s summary
sodium urate from sodium-derived alkaline and the development
of mixed stones [180]. Uric acid (UA) is the end-product of purine metabolism in
Magnesium deficiency increases aldosterone secretion, increas- humans. It is a natural antioxidant that accounts for
ing K+ loss and thus possibly triggering the onset of gout. approximately 60% of plasma antioxidant activity. About
Conversely, administration of spironolactone, which is potassium two-thirds the total body UA pool comes from the
sparing, improves juvenile arthritis and other types of rheumatoid endogenous nucleic acid metabolism, while the remaining
arthritis [60] because of its aldosterone-antagonistic effect, which third comes from diet, particularly purine-rich diets includ-
improves plasma K+ levels. Foods and food products rich in ing meats, meat products, seafood, and sugars (e.g.,
potassium and magnesium can ameliorate hyperuricemia and sucrose, fructose, and glucose). About 70% of the UA
excreted is done so via the kidneys, whereas the remaining
associated complications, including UA lithiasis and gout. Although
30% is excreted via other means. Under normal conditions
potassium therapy is effective for ameliorating hyperuricemia and and with minimal exposure to confounding factors, normal
gout, there are possible adverse effects; therapy is contraindicated serum UA levels range from 2–7 mg/dL (120–420 mmol/L) in
in patients with hyperkalemia, chronic kidney disease, cardiomy- men and 2–6.5 mg/dL (120–390 mmol/L) in women. Serum
opathy, reduced glomerular filtration rate (i.e., creatinine >2.5 mg/ UA levels persistently below and above these ranges are
dL) and in patients on K+-sparing diuretics. Others contra- defined as hypouricemia and hyperuricemia, respectively.
indications include gastritis, peptic ulcer, and associated symp- Diet is strongly implicated in the pathogenesis of abnormal
toms. serum UA levels. Diet components known to increase serum
UA levels include meat, meat products, seafood, beer,
spirits, fructose, and high fructose corn syrup. Meanwhile,
components that modulate serum UA levels include
3.4.2. Sodium vegetables, fruits, coffee, dairy, cherries, vitamin C, protein,
Similarly, sodium citrate may provide an alkaline urinary fiber, and foods that increase basicity. Diets can reduce or
environment necessary for increase UA excretion. However, the increase UA production and/or enhance or inhibit UA
use of sodium citrate is not supported because of its associated excretion. Dietary intervention is universally adopted as
complication of increasing urinary monosodium urate, which the only non-drug-based approach that can be used for the
promotes calcium oxalate crystallization, leading to calcium long-term prevention, control, and management of abnor-
nephrolithiasis [184]. mal serum UA and associated complications such as gout in
humans.

3.4.3. Calcium
The association of dietary calcium with serum UA levels is
inconclusive [81]. Schmidt et al. [76] recently showed that dietary References
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