Dec. 12, 2017
in Mediterranean Diet and Gouty Arthritis
The Mediterranean diet has been
related to longevity and quality of life, which reflects dietary habits of
several countries in the Mediterranean Basin during the early 1960s, some
countries of northern Europe, such as France, Italy, Greece, and Spain (Serra-Majem,
Roman, & Estruch, 2006; A. Trichopoulou & Lagiou, 1997; Antonia
Trichopoulou et al., 2014). In 1993, Oldways working with
Harvard School of Public Health and the WHO created the Mediterranean Diet
Pyramid, in which an emphasis on activity and social interactions were the base
of the pyramid; the main foods included whole grains, fruits, vegetables,
beans, herbs, spices, nuts, legumes, and healthy fats such as olive oil; fish and
seafood especially should be eaten at least twice a week with dairy foods, like
fermented dairy frequently; still consumed eggs and occasionally ate poultry
but limited red meat and sweets; and water and wine were typical beverages (“Mediterranean Diet,” n.d.; “Mediterranean Diet
pyramid,” n.d.). Moreover, the Mediterranean diet has been shown
favorable influences on lipoprotein levels, diabetes and antioxidative
capacity, cardiovascular diseases, arthritis, cancer, body composition, and
psychological function (Serra-Majem
et al., 2006).
However, this research will focus on
dairy foods, especially fermented yogurt in the Mediterranean diet. Fermented
yogurt is a source rich in proteins, including whey proteins, which could be dissolved
into water, and caseins, which is insoluble milk proteins (“Yogurt 101,” 2014). The majority, almost 80% of
proteins in yogurt are caseins, which could promote the absorption of minerals,
such as calcium and phosphorus (Holt, Carver, Ecroyd, & Thorn, 2013). A small amount, nearly
20% of proteins found in yogurt are whey, which is a popular supply among
bodybuilders and athletes (“Yogurt 101,” 2014). What is more, whey
protein also could supply diverse health benefits, like weight loss (Miller, Alexander, & Perez, 2014) and weight maintaining.
Since both of casein and whey are abundant of essential amino acids, especially
branched-chain amino acids (BCAAs) in whey, these macronutrients are beneficial
for human beings’ digestive system (“Yogurt 101,” 2014). Whereas, two-thirds of
individuals in the United States do not meet the recommendation, three daily
servings of low-fat or no-fat dairy products, recommended by Dietary Guidelines
for Americans (DGA). Strikingly, 90% of children and adults in the U.S. consumed
less than 1 cup of yogurt per week, which is far less than recommended by DGA,
1 serving of yogurt per day (Webb, Donovan, & Meydani, 2014).
Arthritis is inflammation of one or
more of joints, which is a rheumatic condition (“Arthritis,” n.d.). Thus, patients with arthritis
tend to fell pain and aching. Other symptoms involve swelling, stiffness, and
decreased range of motion (“What Is Arthritis?,” n.d.-a). According to the Centers for
Disease Control and Prevention (CDC), it reported that 54.4 million adults in
the United States suffering some forms of arthritis (“Arthritis,” n.d.). People range from all ages,
sexes, and races do have this disease. Moreover, there are over 100 different
types of arthritis and related conditions, including degenerative or mechanical
arthritis (osteoarthritis the most common type), inflammatory arthritis, infectious
arthritis, and metabolic arthritis (“Arthritis,” n.d.).
In this article, it will focus on
metabolic arthritis, which is a condition that uric acid is accumulated in the
body through broking down purines (“Arthritis,” n.d.). If the uric acid level builds up
continuously but not reducing, it will turn to gout, a particular type of
metabolic arthritis (“What Is Arthritis?,” n.d.-b). Diagnosing this kind of arthritis
is complex, while the most reliable method diagnosing gouty arthritis is to do
synovial fluid analysis to detect uric acid or crystal formation levels in
patients’ body (“Gout Symptoms and Diagnosis | Johns Hopkins
Arthritis Center,” n.d.). According to the CDC, it reported
that 8.3 million Americans were influenced by gout (“Gout,” n.d.) and the prevalence of gout among
men is higher than among women in the United States (Hyon
K. Choi, Atkinson, Karlson, Willett, & Curhan, 2004; Zhu, Pandya, &
Choi, 2011). What is more, it is a disease relating to diet
closely, since purines could not only be found in human cells, but also could
be found in several foods, such as red meats, shellfish, purine-rich
vegetables, and so on. Besides these purine-rich foods, some certain foods
could raise the level of uric acid, like alcohol, especially beer, and those
foods containing high amounts of fructose (“What Is Arthritis?,” n.d.-b). However, there is a decrease in the
incidence of gout with increasing low-fat dairy products intake, soy products
intake and vitamin C supplements (Hyon
K Choi, 2010; Garrel et al., 1991; Shulten, Thomas, Miller, Smith, & Ahern,
2009). Importantly, the complications of severe gouty
arthritis could be related to cardiovascular, myocardial infarction (H.
K. Choi & Curhan, 2007; Krishnan, Baker, Furst, & Schumacher, 2006), type 2 mellitus (H.
K. Choi, Vera, A, & Krishnan, 2008) and metabolic disease.
Nevertheless, few studies conducting on the mechanism of dairy products
in gout patients.
Therefore, researchers need to do more research to explore why dairy proteins
have positive impacts on preventing gouty arthritis.
Metabolism of protein
The structure of proteins contains
primary, secondary, tertiary, and quaternary fourth levels. The primary
structure of a protein is the amino acid sequence, which is the basic frame of
proteins; the secondary structure of a protein is coiling, folding, interacting
between and among amino acids; the tertiary structure of a protein is a
three-dimensional configuration, which is a higher level of proteins; and the
quaternary structure is two or more polypeptide chains interacting together,
which is the highest structure of a protein. Amino acids are the building
blocks in forming the primary structure of a protein, which contains at least
one amino group (-NH2), at least one acid group (-COOH), and a side
chain (R group) structurally.
few digestions of proteins happen in mouth and esophagus, the onset of
digestion starts at stomach. Because of the internal environment of stomach, gastric pH less than 3, which caused by
hydrochloric acid (HCl) presenting in gastric juice, proteins will be denatured
to the primary structure through quaternary, tertiary, and secondary structures
of protein. While, the primary structure of proteins could not be affected by
the hydrochloric acid, on the other hand, hydrochloric acid could activate
pepsin from pepsinogen. Pepsin is an endopeptidase actively around pH
less than about 3.5, attacking peptide bonds adjacent to the carbaoxy end of
long amino acid chains. The products of protein end in stomach including large
polypeptides primarily, oligopeptides and free amino acids.
The further digestion occurs in the
small intestine, firstly in the duodenum. In the duodenum, proteins and
polypeptides could be further digested with the release of pancreatic juice and
zymogens. In the small intestine, several zymogens function the important roles
in this digestion process; to be more specific, a couple of peptidases are produced
by enterocytes. The end
products of this process are peptides and free amino acids, which could be
absorbed by human beings’ body. The most of amino acids are absorbed in the
duodenum and jejunum across the brush border membrane through carriers. The
peptide, especially dipeptide and tripeptide, also need a transport system, but
through different transporters. After these products enter the enterocyte, they
continue to transport into blood for use across basolateral membrane. And then through
capillaries of the villi enter into blood, flowing in the blood stream to liver,
kidney, and other organs.
Actually, protein could not be
stored in tissues of the body, however, they are in continuous breakdown and
synthesis cycling, which called protein turnover. The liver is the primary site
of amino acids metabolism. The first step of amino acid catabolism involves
transamination or deamination process. Transamination reactions contain
transferring an amino group from an amino acid to an a-keto acid. Contrary
to transamination reactions, deamination process involves only removing the
amino groups from amino acids, releasing nitrogen as ammonia. Ammonia could be detoxified
through a couple of pathways. For the remaining part, a-keto acid, has
multiple uses in cells by further metabolism. Through various reactions, amino
acid could be converted to pyruvate, acetyl CoA, and the intermediates of TCA
cycle to generate energy. They also could be utilized for glucose, ketone body,
cholesterol, and fatty acid production depending on the original amino acid
Hormones have an influential role in
controlling over the protein balance in the body. For catabolic process, stimulated
by cortisol and the higher ratio of glucagon-to-insulin in the blood. In contrast
to degradative process, insulin could increase protein synthesis, and decrease
protein degradation to rise the blood concentration of amino acid.
One possible metabolism of milk
protein protecting gouty arthritis is the urate-lowing effect (Hyon K. Choi et al., 2004; Dalbeth & Palmano,
2011). Since naturally
bovine milk is low-purine products, which also could decline serum urate by
about 10% (Dalbeth & Palmano, 2011). Meanwhile, dairy products excrete
segmental uric acid rapidly. Combined with the feature and the function, all
milk products have the feature of reduction of serum urate concentrations.
Review of literature
Several studies have been shown
adherence to the Mediterranean diet has a potential relationship with serum
uric acid levels (Kontogianni
et al., 2012), which could reduce the likelihood
of having gouty arthritis. Specifically, focused on moderated dairy products
provided in Mediterranean diet, there are a couple of research suggesting increased
dairy intake negatively associated with the incident of gout (Dalbeth
& Palmano, 2011; Kontogianni et al., 2012; Singh, Reddy, & Kundukulam,
2011), especially low-fat dairy products (Kontogianni
et al., 2012).
The potential reasons of inverse
relationship between milk intake and serum uric acid level, involved the
composition of bovine milk, and the metabolism of milk protein in the human
being’s body (Dalbeth
& Palmano, 2011). Firstly, all milks have an effect
on decrease serum urate. Orotic acid in bovine milk is a uricosuric compound to
transport out uric acid through kidney, which resulting in decreasing the
reabsorption of uric acid (Dalbeth,
Wong, et al., 2010). On the other hand, milk products
could improve the fractional execration of uric acid (FEUA) rapidly. The higher
rate excretion of uric acid through kidney, the lower level of serum urate
flowing in the body. Additionally, dairy products also promote the excretion of
xanthine, which is a precursor of urate. With the reduction of xanthine, serum
urate level subsequently decreased to avoid serum urate crystals formation.
reliable diagnosis of gouty arthritis is testing the uric acid level present in
blood through synovial fluid analysis. Uric acid could be produced from the
endogenous purine metabolism, and from the end products of exogenous foods,
such as milk protein (Maiuolo,
Oppedisano, Gratteri, Muscoli, & Mollace, 2016).
In addition, anti-inflammatory
properties of some particles in milk might contribute to the decrease of the
risk of gouty arthritis. Such as glycolmacropeptide and G600 milk fat extract
could inhibit the inflammatory response of monosodium urate (MSU) crystals within
the joint (Dalbeth
& Palmano, 2011). The initial process of
inflammatory response caused by macrophages phagocytosing MSU crystals, which
activated and release a high-molecular, interleukin (IL)-1b.
Activated IL-1b continuous caused release of
several pro-inflammatory cytokines, like IL-8, TNF-a.
Finally, neutrophils are recruited of inflammatory cells in the joint (Gonzalez,
2012). According to Dalbeth,
Gracey, et al. (2010), certain dairy fractions could
regulate the inflammatory response of gout. Glycolmacropeptide could inhibit
IL-1b gene expression in the THP-1 cells. Moreover, G600
milk fat extract inhibit IL-8 protein expression in the THP-1 cells (Dalbeth
& Palmano, 2011).
What is next?
There is still a lot of research
needed to be done on the pathology of gouty arthritis, and the detail
metabolism of milk protein in preventing the risk of the gout. Since the
pathology of hyperuricemia is controversial, some patients with hyperuricemia
did not have the gout simultaneously.
Thus, the pathology of gout need to be explored continuously. What is more, a
couple of studies conclude that there is an inverse association between the
dairy intake and serum uric acid level. However, very few research could tell
why there is a relationship between these two substances, and no research
identify the specific metabolism during this process. Therefore, it is
necessary to do more research to explore the detail pathway within this investigation.
Considering inflammatory factors, poorly
understood of the molecular component of the inflammation recently (Gonzalez,
2012), the effects of glycolmacropeptide and G600 milk fat
extract required further exploration.
A further issue is to make the
recommendation according to diet for gouty patients. Although it is important
to modify the dietary pattern for preventing the gout, there is no
recommendation on how much patients should consume each day. Meanwhile, few
intervention studies have conducted and examined the modification dietary in
patients with gouty arthritis. Thus, more research studied in this area could
help investigators and patients with gout understand and manage this disease successfully.
A couple of research suggested that
adherence to Mediterranean diet could lower the likelihood of having gouty
arthritis, which caused by hyperuricemia. To be more specific, the increase in
dairy intake has a negative association with serum uric acid level. Since the
dairy products are low in purine content, simultaneously, milk products are featured with
urate-lowering effects. Moreover, the anti-inflammatory factors in bovine milk
also play significant roles in decreasing the risk of gouty arthritis. Nevertheless,
more research needed to be done in pathology and detail metabolism with dairy
protein and gout to help followings and patients to manage this disease
Causes, types, and treatments. (n.d.). Retrieved November 30, 2017, from
Choi, H. K. (2010). A prescription for lifestyle
change in patients with hyperuricemia and gout: Current Opinion in
Rheumatology, 22(2), 165–172. https://doi.org/10.1097/BOR.0b013e328335ef38
Choi, H. K., Atkinson, K., Karlson, E. W., Willett,
W., & Curhan, G. (2004). Purine-Rich Foods, Dairy and Protein Intake, and
the Risk of Gout in Men. The New England Journal of Medicine; Boston, 350(11),
Choi, H. K., & Curhan, G. (2007). Independent
Impact of Gout on Mortality and Risk for Coronary Heart Disease. Circulation,
116(8), 894–900. https://doi.org/10.1161/CIRCULATIONAHA.107.703389
Choi, H. K., Vera, D., A, M., & Krishnan, E.
(2008). Gout and the risk of type 2 diabetes among men with a high
cardiovascular risk profile. Rheumatology, 47(10), 1567–1570.
Dalbeth, N., Gracey, E., Pool, B., Callon, K.,
McQueen, F. M., Cornish, J., … Palmano, K. (2010). Identification of dairy
fractions with anti-inflammatory properties in models of acute gout. Annals
of the Rheumatic Diseases; London, 69(4).
Dalbeth, N., & Palmano, K. (2011). Effects of
Dairy Intake on Hyperuricemia and Gout. Current Rheumatology Reports, 13(2),
Dalbeth, N., Wong, S., Gamble, G. D., Horne, A.,
Mason, B., Pool, B., … Palmano, K. (2010). Acute effect of milk on serum urate
concentrations: a randomised controlled crossover trial. Annals of the
Rheumatic Diseases; London, 69(9).
Garrel, D. R., Verdy, M., PetitClerc, C., Martin,
C., Brulé, D., & Hamet, P. (1991). Milk- and soy-protein ingestion: acute
effect on serum uric acid concentration. The American Journal of Clinical
Nutrition, 53(3), 665–669.
Gonzalez, E. B. (2012). An update on the pathology
and clinical management of gouty arthritis. Clinical Rheumatology, 31(1),
Gout Symptoms and Diagnosis | Johns Hopkins
Arthritis Center. (n.d.). Retrieved November 30, 2017, from
Gout: Symptoms, causes, and treatment. (n.d.).
Retrieved December 6, 2017, from
Holt, C., Carver, J. A., Ecroyd, H., & Thorn,
D. C. (2013). Invited review: Caseins and the casein micelle: their biological
functions, structures, and behavior in foods. Journal of Dairy Science, 96(10),
Kontogianni, M. D., Chrysohoou, C., Panagiotakos,
D. B., Tsetsekou, E., Zeimbekis, A., Pitsavos, C., & Stefanadis, C. (2012).
Adherence to the Mediterranean diet and serum uric acid: the ATTICA study. Scandinavian
Journal of Rheumatology, 41(6), 442–449.
Krishnan, E., Baker, J. F., Furst, D. E., &
Schumacher, H. R. (2006). Gout and the risk of acute myocardial infarction. Arthritis
& Rheumatism, 54(8), 2688–2696.
Maiuolo, J., Oppedisano, F., Gratteri, S., Muscoli,
C., & Mollace, V. (2016). Regulation of uric acid metabolism and excretion.
International Journal of Cardiology, 213(Supplement C), 8–14.
Mediterranean Diet. (n.d.). Retrieved November 29,
2017, from https://oldwayspt.org/traditional-diets/mediterranean-diet
Mediterranean Diet pyramid. (n.d.). Retrieved
November 29, 2017, from
Miller, P. E., Alexander, D. D., & Perez, V.
(2014). Effects of whey protein and resistance exercise on body composition: a
meta-analysis of randomized controlled trials. Journal of the American
College of Nutrition, 33(2), 163–175.
Serra-Majem, L., Roman, B., & Estruch, R.
(2006). Scientific Evidence of Interventions Using the Mediterranean Diet: A
Systematic Review. Nutrition Reviews, 64, S27–S47.
Shulten, P., Thomas, J., Miller, M., Smith, M.,
& Ahern, M. (2009). The role of diet in the management of gout: a
comparison of knowledge and attitudes to current evidence. Journal of Human
Nutrition and Dietetics: The Official Journal of the British Dietetic
Association, 22(1), 3–11.
Singh, J. A., Reddy, S. G., & Kundukulam, J.
(2011). Risk factors for gout and prevention: a systematic review of the
literature: Current Opinion in Rheumatology, 1.
Trichopoulou, A., & Lagiou, P. (1997). Healthy
traditional Mediterranean diet: an expression of culture, history, and
lifestyle. Nutrition Reviews, 55(11 Pt 1), 383–389.
Trichopoulou, A., Martínez-González, M. A., Tong,
T. Y., Forouhi, N. G., Khandelwal, S., Prabhakaran, D., … de Lorgeril, M.
(2014). Definitions and potential health benefits of the Mediterranean diet:
views from experts around the world. BMC Medicine, 12.
Webb, D., Donovan, S. M., & Meydani, S. N.
(2014). The role of Yogurt in improving the quality of the American diet and
meeting dietary guidelines. Nutrition Reviews, 72(3), 180–189.
What Is Arthritis? (n.d.-a). Retrieved November 30,
What Is Arthritis? Symptoms, Diet, Treatment &
Types. (n.d.-b). Retrieved November 30, 2017, from
Yogurt 101: Nutrition Facts and Health Benefits.
(2014, November 7). Retrieved November 29, 2017, from
Zhu, Y., Pandya, B. J., & Choi, H. K. (2011).
Prevalence of gout and hyperuricemia in the US general population: The National
Health and Nutrition Examination Survey 2007–2008. Arthritis &
Rheumatism, 63(10), 3136–3141. https://doi.org/10.1002/art.30520