What is gout and how is it treated?

Long ago gout earned its royal nickname because only the wealthy could afford the rich food that seemed to trigger the condition. Nowadays we can all eat like the kings of the past and, not surprisingly, gout is becoming increasingly common.

What is gout?

Gout is an excruciatingly painful condition that usually begins in the big toe and sometimes spreads to other joints. Gout is caused by a high level of uric acid in the bloodstream (hyperuricemia) but gout itself does not actually occur until the uric acid crystalizes. Normally uric acid is dissolved in the blood and passed through the kidneys into the urine, where it is eliminated. However, once uric acid levels rise above the “saturation point” (approximately 350 to 420 µmol/l), needle sharp crystals of monosodium urate can precipitate out and build up in the joints (2). Painful symptoms usually strike during the night and get worse over the next 8 to 12 hours. Symptoms gradually ease and disappear in 7 to 10 days. 60% of people who have an attack will have a second one within a year and 84% will have another attack within three years. This is because the urate crystals do not disappear even when the pain goes away and they will cause low-level inflammation that continues to slowly damage the joint (6). Most animal species have enzymes in their bodies to help eliminate uric acid. Humans, however, along with insects, birds and reptiles, appear to conserve uric acid because it acts as an anti-oxidant that assists in scavenging harmful free radicals in the body (7). Although normal levels of uric acid are helpful, higher levels increase risk of gout.

The woes of the big toe
It seems that the big toe, languishing far away from the core of the body at the end of the foot, is ideally situated for the formation of urate crystal build-up. It tends to exist at a lower temperature and, because of its expansive range of motion as it swings around on the end of the leg, it is more vulnerable to both the effects of gravity and the potential of injury (toe stubbing) that promotes the development of osteoarthritis, all factors that add to its greater tendency to develop crystals in its joint (8).

Gout as a chronic problem
Uncontrolled hyperuricemia can lead to development of tophi, permanent lumpy swellings containing aggregates of urate crystals. These can be large and painful and may damage nearby bone tissue. Tophi are relatively rare now due to the availability of drugs that control uric acid levels (11).

Why do we get gout?
The excess level of uric acid in the blood is almost always the result of one or both of the following conditions;

• Increased production of uric acid due to either the breakdown of DNA and RNA molecules in our own body (purine metabolism) or the excessive ingestion of purine in the diet. Purines are the building blocks of DNA and as such are present in all body tissues. Our bodies continually process purines, unravelling them and converting them into by-products to be removed from the body. Uric acid is one of these by-products and is excreted from the body through the urine (11). Another source of purine for humans is the foods that we eat. Purine is found in both animal and plant foods in varying amounts.

• Decreased excretion of uric acid in the urine by the kidneys (1,2)

Some factors that increase the risk of gout (6);
Genetics – Although your genes account for only about 6% of the variation in blood uric acid amongst different people, they are a factor that can increase risk for gout. In 90% of cases, genetic risk affects the kidneys and results in a decrease of the elimination of uric acid through urine (3).
Gender and age – Gout is more common in men until about the age of 60. Estrogen seems to protect women from gout until menopause by increasing the elimination of uric acid in the urine. After menopause the incidence of gout increases in women to equal that of men.
Other medical conditions – Heart disease, hypertension, diabetes, obesity, kidney disease and elevated lipid levels are all associated with higher incidence of gout. As we are finding out, most of these chronic diseases are directly related to eating a high-fat Western diet. The increase in the prevalence of end-stage kidney disease caused by an unhealthy diet may be one cause for the recent increases in gout incidence (10). Obese people are at higher risk for gout and develop gout at a younger age than people of normal weight. New research on the obese and their gout experiences is focussing on fatty acids, such as those obtained from eating high-fat meals Fatty acids add their own pro-inflammatory effects to the uric acid crystals in the joints which increase the pain that occurs with gout (29).
Medications – Diuretics (“water pills”, especially hydrochlorothiazide and furosemide), methotrexate (used for rheumatoid arthritis), low-dose aspirin (9) and immune suppressants taken by transplant patients (such as cyclosporine) can raise the risk of gout.
Diet – Diet choices make a huge difference in both uric acid levels and gout. (See Part Two of this article)

A SHORT PRIMER ON GOUT MEDICATIONS (32)

Drugs for immediate, short-term pain relief;
NSAIDs (ex – indomethacin, ibuprofen, naproxen, diclofenac) – Non-steroidal anti-inflammatory drugs are usually the first choice for pain and inflammation relief in gout. The sooner you take them after gout pain starts, the better they work. NSAIDS do not reduce uric acid level so they do not get rid of urate crystals or prevent joint damage. NSAIDS can cause digestive tract problems (stomach upset, gastrointestinal ulcers and or bleeding). They also bring with them a small increased risk of heart attack or stroke and worsening of kidney disease.
Reasons to avoid NSAIDs include
• Smoking, circulation problems, high blood pressure, high cholesterol, diabetes
• Interaction with medications such as “water pills” or warfarin

Colchicine – Colchicine is derived from the crocus plant. It is good for easing the inflammation caused by urate crystals in a joint, however it helps only about 70% of those who take it. Colchicine needs to be started as close as possible to the beginning of an attack of gout otherwise it does not work. The most common side effects are nausea, vomiting and diarrhea, especially at higher doses. Unfortunately, colchicine has a narrow therapeutic index, meaning that there is no clear-cut distinction between nontoxic, toxic, and lethal doses. Unintentional toxicity is common and often associated with a poor outcome (34). To limit both possible side effects and possible poisoning, it is best to start at a low dose and increase the dose once no adverse effects have appeared. Colchicine can also be taken daily to prevent future attacks.
Colchicine should not be taken at the same time as NSAIDs. Colchicine can interact with many other drugs (including statins for high cholesterol) but your doctor may be able to temporarily adjust dosages of your other medications to allow temporary colchicine use.
Like NSAIDs, colchicine does not reduce uric acid level, prevent the formation of urate crystals or prevent long-term joint damage.

Corticosteroids (ex – prednisone, methylprednisolone) – These medications can be taken by mouth or by injection to reduce inflammation caused by acute gout attacks. They are usually reserved for those who cannot take NSAIDs or colchicine. Corticosteroids have numerous side effects which include sleep disturbance, gastrointestinal upset, weight gain and restlessness.

Other treatments – An ice pack on the affected area can reduce swelling and pain. Be sure to wrap the pack with a damp towel to avoid irritating the skin.
Rest for the affected area will help reduce severe pain.
Using a cage over the involved part to remove the weight of bedclothes can also be helpful.

Drugs for long-term treatment;
Long-term gout treatments strive to prevent future attacks by keeping blood uric acid levels below their saturation point (the point at which crystals start to develop). Long-term treatments are only started if diet and lifestyle changes are not enough. (See Part Two of this article for more information.) It may take longer than six months of a long-term medication to dissolve away all the uric acid crystals and abort the possibility of further gout attacks.

Allopurinol – This medication is the first choice for lowering uric acid level. It is generally started at a low dose and increased slowly in order to prevent acute attacks that might occur as the crystals break down and move through the body. Often it is prescribed at a dose of 300 mg or less per day but, according to clinical studies, a dose of 400 mg per day is needed in 90% of patients to actually decrease the uric acid level below 360 µmol/l, the goal for a healthy uric acid level. Once the blood uric acid reaches the desired level, the patient must continue taking the same dose, having blood tests every year to make sure the uric acid levels are still in the desired range.
Allopurinol has been used for many years and has displayed a good safety profile. Apart from occasional skin rashes, it appears to have remarkably few side effects, although rarely it can cause headaches or nausea when first started.
Allopurinol works by reducing the amount of uric acid the body makes by inhibiting xanthine oxidase, an enzyme that helps convert purine into uric acid. Allopurinol is broken down and excreted by the kidneys so lower doses must be used in impaired kidney function.
Allopurinol can interact with other drugs.
Allopurinol can inhibit the metabolism of warfarin and enhance its anticoagulant effect.
Because allopurinol inhibits xanthine oxidase, an enzyme which also inactivates the drug azathioprine, such a combination can result in a reduction in the production of white blood cells. This can be life threatening.
In many cases the doses of each interacting drug can be adjusted to allow drugs to work effectively together.

Feboxostat (Uloric) – This medication is a more recent addition to the arsenal for the prevention of gout attacks. It is about ten to twenty times more expensive than allopurinol. Its advantage is that its dose does not need to be adjusted for patients with kidney disease. Possible side effects are hypertension, dizziness, nausea, increased cardiac events (such as strokes, heart attacks and death) and adverse effects on the liver.

Uricosuric drugs (ex – probenecid) – These medications work by flushing out more uric acid than normal through the kidneys. They are only used when allopurinol is not suitable for a particular person.

How long must I take my gout medication?
Allopurinol, the most common uric acid lowering medication, is often taken for life. Once the proper dose is determined through monitoring of the blood uric acid level, that dose must be continued. A blood test is then performed yearly to be sure the blood uric acid is remaining at an optimum low level. For many patients, uric acid levels will never fall back to safe levels without the help of a drug such as allopurinol. However, high uric acid has many causes and some are reversible. Removing the cause may mean reducing the allopurinol dose or discontinuing it altogether (33).

It is very important to consider other ways of reducing uric acid levels if your goal is leaving allopurinol therapy behind. Diet and lifestyle changes that can improve uric acid levels and gout will be covered in Part Two of this article.

SOURCES:
1 Barr, W.G. Clinical Methods: The History, Physical, and Laboratory Examinations. Editors: Walker, H.K., Hall, W.D., Hurst, J.W.3rd edition. Boston: Butterworths; 1990. Chapter 165.

2 Gonzalez, E.B. An update on the pathology and clinical management of gouty arthritis. Clin Rheumatol. 2012 Jan; 31(1):13-21.

3 Reginato, A.M., Mount, D.B., Yang, I., Choi, H.K. The genetics of hyperuricaemia and gout. Nat Rev Rheumatol. 2012 Oct; 8(10):610-621.

4 Choi, H.K., Atkinson, K., Karlson, E.W., Willett, W., Curhan,G. Purine-Rich Foods, Dairy and Protein Intake, and the Risk of Gout in Men. N Engl J Med 2004; 350:1093-1103.

5 Zhang, Y., Chen, C., Choi, H. et al. Purine-rich foods intake and recurrent gout attacks. BMJ Ann Rheum Dis. 2012 Sep; 71(9):1448-1453.

6 www.arthritis.org Arthritis Foundation, National Office – Atlanta, GA, USA

7 Ames, B.N., Cathcart, R., Schwiers, E., Hochstein, P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. 1981 Nov; 78(11): 6858–6862.

8 Roddy, E. Revisiting the pathogenesis of podagral: why does gout target the foot? J Foot Ankle Res. 2011; 4: 13.

9 Caspi, D., Lubart, E., Graff, E., Habot, B., Yaron, M., Segal, R. The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients. Arthritis Rheum 2000; 43:103–108.

10 Roddy, E., Zhang, W., Doherty, M. The changing epidemiology of gout. Nat Clin Pract Rheumatol 2007; 3:443–449.

11 http://www.health.harvard.edu/newsletter_article/all-about-gout

12 Dalbeth, N., Ames, R., Gamble, G.D., et al. Effects of skim milk powder enriched with glycomacropeptide and G600 milk fat extract on frequency of gout flares: a proof-of-concept randomised controlled trial. Ann Rheum Dis. 2012 Jun; 71(6):929-934.

13 Dalbeth, N., Wong, S., Gamble, G.D. et al. Acute effect of milk on serum urate concentrations: a randomised controlled crossover trial. Ann Rheum Dis. 2010 Sep; 69(9):1677-1682.

14 Choi, H.K., Curhan, G. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. Br Med J 2008; 336:309–312.

15 Underwood, M. Sugary drinks, fruit, and increased risk of gout. Br Med J 2008; 336:285–286.

16 Gao, X., Curhan, G., Forman, J.P., Ascherio, A., Choi, H.K. Vitamin C intake and serum uric acid concentration in men. J Rheumatol 2008; 35:1853–1858.

17 Huang, H.Y., Appel, L.J., Choi, M.J. et al. The effects of vitamin C supplementation on serum concentrations of uric acid: results of a randomized controlled trial. Arthritis Rheum 2005; 52:1843–1847.

18 Jacob, R.A., Spinozzi, G.M., Simon, V.A. et al. Consumption of cherries lowers plasma urate in healthy women. J Nutr 2003; 133:1826–1829.

19 Kiyohara, C., Kono, S., Honjo, S. et al. Inverse association between coffee drinking and serum uric acid concentrations in middle-aged Japanese males. Br J Nutr 1999; 82:125–130.

20 Choi, H.K., Willett, W., Curhan, G. Coffee consumption and risk of incident gout in men: a prospective study. Arthritis Rheum 2007; 56:2049–2055.

21 Williams, P.T. Effects of diet, physical activity and performance, and body weight on incident gout in ostensibly healthy, vigorously active men. Am J Clin Nutr 2008; 87:1480–1487.

22 Choi, H.K., Atkinson, K., Karlson, E.W., Willett, W., Curhan, G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004; 363:1277–1281.

23 Kanbara, A., Miura, Y., Hyogo, H., Chayama, K., Seyama.I. Effect of urine pH changed by dietary intervention on uric acid clearance mechanism of pH-dependent excretion of urinary uric acid. Nutr J. 2012 Jun 7; 11:39.

24 Zgaga, L., Theodoratou, E., Kyle, J., Farrington, S.M., et al. The Association of Dietary Intake of Purine-Rich Vegetables, Sugar-Sweetened Beverages and Dairy with Plasma Urate, in a Cross-Sectional Study. PLoS One. 2012; 7(6): e38123.

25 Desideri, G., Castaldo, G., Lombardi, A., Mussap, M. et al. Is it time to revise the normal range of serum uric acid levels? Eur Rev Med Pharmacol Sci. 2014;18(9):1295-1306.

26 Singh, J.A., Reddy, S.G., Kundukulam, J. Risk factors for gout and prevention: a systematic review of the literature. Curr Opin Rheumatol. 2011 Mar; 23(2):192-202.

27 Teng, G.G., Pan, A., Yuan, J.M., Koh, W.P. Food sources of protein and risk of incident gout in the Singapore Chinese Health Study. Arthritis Rheumatol 2015 Jul; 67(7): 1933-1942

28 Rai, S.K., Fung, T.T., Lu, N., Keller, S.R., Curhan, G.C., Choi, H.K. The Dietary Approaches to Stop Hypertension (DASH) diet, Western diet, and risk of gout in men: prospective cohort study. BMJ 2017; 357:j1794.

29 Cronstein, B.N., Sunkureddi, P. Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis. J Clin Rheumatol. 2013 Jan; 19(1):19-29.

30 http://www.brendadavisrd.com/plant-based-diets-and-gout/

31 https://www.healthlinkbc.ca/

32 http://www.arthritisresearchuk.org/arthritis-information/conditions/gout/treatments

33 Perez-Ruiz, F., Atxotegi, J., Hernano, I. et al. Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long-term urate-lowering therapy: a prospective study. Arthritis Rheum. 2006 Oct 15; 55(5):786-790.

34 Finkelstein, Y., Aks, S.E., Hutson, J.R. et al. Colchicine poisoning: the dark side of an ancient drug. Clin Toxicol (Phila). 2010 Jun; 48(5):407-414.

35 Kelley, D.S., Rasooly, R., Jacob R.A., Kader, A.A., Mackey, B.E. Consumption of Bing sweet cherries lowers circulating concentrations of inflammation markers in healthy men and women. J Nutr. 2006 Apr; 136(4):981-986.

36 Zhang, Y., Neogi, T., Chen, C. et al. Cherry Consumption and decreased risk of recurrent gout attacks. Arthritis Rheum. 2012 Dec; 64(12):4004-4011.

37 Schlesinger, N., Schlesinger, M. Pilot Studies of Cherry Juice Concentrate for Gout Flare Prophylaxis. J Arthritis 2013 Apr; 65(4):1135-1136.