Gout

• 1. Two O'Clock in the Morning

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  Gout is a painful form of arthritis, and in 1683 the English physician Thomas Sydenham wrote down exactly how an attack begins. A man goes to bed in good health and sleeps soundly. About two o'clock in the morning, Sydenham reported, he is awakened by a severe pain in the great toe. The pain feels like a dislocation, he added, yet the area feels as if cold water were poured over it. Chills, shivers and a little fever follow, and the night passes in torture and sleeplessness.

  This documentary asks what is actually happening inside that toe. It asks why such an attack so often arrives in the dark hours, and why some people are far more prone to it than others. It also asks how an ancient ailment came to carry a reputation tied to wealth. The answers run through blood chemistry, a handful of genes, the contents of a dinner plate, and the evolutionary history of apes.

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• 2. Anatomy of an Attack

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  Doctors describe the classic gout attack as a single joint that turns red, tender, hot and swollen, with pain that typically reaches its worst in less than 12 hours. The joint at the base of the big toe, called the metatarsophalangeal joint, is affected in about half of cases. This pattern has its own name, podagra. Gout can also involve the midfoot, including the cuneiform bones, as well as the heels, knees, wrists and fingers.

  Doctors blame lower body temperature for the night-time start. Fatigue and high fever may occasionally accompany the joint pain, but they are rare.

  Left untreated, a single attack usually fades in five to seven days. Even so, 60% of people have a second attack within a year.

  Years of elevated uric acid can leave behind tophi, which are hard, painless deposits of uric acid crystals. Among people untreated for five years, 30% develop them. Tophi often appear in the helix of the ear, over the olecranon processes, the bony tips of the elbows, or on the Achilles tendons. Extensive tophi can erode bone, leading to chronic arthritis, destroyed joint surfaces and joint deformity. With aggressive treatment, tophi may dissolve.

  Kidney stones complicate gout in between 10 and 40% of people. They form because low urine pH encourages uric acid to precipitate. Crystals lodging in the kidneys can also bring on acute uric acid nephropathy, a form of kidney damage.

  People with gout face a higher risk of hypertension, diabetes, kidney disease and cardiovascular disease, and therefore a higher risk of death. Part of that risk is tied to insulin resistance and obesity, but some of it appears to be independent of both.

  The tophi and the stones are built from the same waste product, and the way it turns solid inside the body involves one particular immune alarm.

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• 3. Crystals and Inflammation

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  Uric acid is the final product of purine metabolism, and gout begins when it crystallizes as needle-shaped monosodium urate. The crystals settle as tophi in joints, along tendons and in the surrounding tissues.

  A ring of proteins can wall off microscopic tophi. That ring keeps the crystals away from the body's cells, so no inflammation results. Trouble starts when naked crystals break out. Minor physical damage to the joint, medical or surgical stress, or rapid swings in uric acid levels can set them loose.

  Once free, the crystals meet macrophages, immune cells that respond by starting a local inflammatory reaction. A protein complex called the NLRP3 inflammasome sets that reaction off. It recruits an enzyme, caspase 1, which converts pro-interleukin 1β into active interleukin 1β, one of the key proteins in the inflammatory cascade.

  The triggers for precipitation are not well understood. Uric acid may crystallize even at normal levels, though it is more likely to do so as levels climb. Cool temperatures are among the suspected triggers, and the extra precipitation at low temperatures partly explains why the joints of the feet suffer most. Acidosis, articular hydration and extracellular matrix proteins are also thought to matter.

  Chemotherapy and diuretics can also change uric acid levels rapidly. The same logic applies to medicine meant to help, because starting or increasing a urate-lowering drug can itself bring on an attack, and febuxostat carries a particularly high risk.

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• 4. Why Uric Acid Rises

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  In about 90% of cases of high blood uric acid, the kidneys are underexcreting it, while overproduction explains fewer than 10%. Only about 10% of people with this condition, called hyperuricemia, go on to develop gout. The odds depend on how high the level climbs. At 415 to 530 micromoles per litre, which is 7 to 8.9 milligrams per decilitre, the risk is 0.5% per year. Above 535 micromoles per litre, or 9 milligrams per decilitre, it rises to 4.5% per year.

  Genes account for roughly 60% of the variability in uric acid level. Three genes, SLC2A9, SLC22A12 and ABCG2, are commonly linked with gout, and variations in them can approximately double the risk. Loss-of-function mutations in SLC2A9 and SLC22A12 lower blood uric acid by reducing urate absorption, which leaves urate secretion unopposed. Rare inherited disorders, including Lesch-Nyhan syndrome, which involves hypoxanthine-guanine phosphoribosyltransferase deficiency, also come with gout.

  Diet explains about 12% of gout. Alcohol, sugar-sweetened beverages, meat and seafood show strong associations. The foods richest in purines include dried anchovies, shrimp, organ meat, dried mushrooms, seaweed and beer yeast, and chicken and potatoes also appear related.

  Studies in the early 2000s cleared several suspects. Beans, peas, lentils and spinach, all purine-rich vegetables eaten in moderation, are not associated with gout, and neither is total dietary protein. Alcohol remains strongly linked to risk, with wine somewhat less risky than beer or spirits.

  Physical fitness, a healthy weight and low-fat dairy products appear to lower the risk of gout. Coffee and vitamin C help to a lesser extent, though vitamin C supplements do not seem to make a significant difference once gout is established. Peanuts, brown bread and fruit also look protective, partly by reducing insulin resistance. Cherries may help prevent attacks. So may avoiding alcohol entirely and cutting back on fructose from sucrose and high fructose corn syrup. Skim milk powder enriched with glycomacropeptide and G600 milk fat extract may reduce pain, at the price of diarrhea and nausea.

  High ambient temperature and low relative humidity may raise the chance of a recurrence.

  Metabolic syndrome occurs in nearly 75% of cases. It is a cluster of abdominal obesity, hypertension, insulin resistance and abnormal lipid levels. A body mass index of 35 or more triples a man's risk. Gout also commonly accompanies lead poisoning, kidney failure, hemolytic anemia, psoriasis, solid organ transplants and myeloproliferative disorders such as polycythemia. Chronic lead exposure and lead-contaminated alcohol raise the risk because lead harms kidney function.

  Diuretics have been associated with attacks, although a low dose of hydrochlorothiazide does not seem to raise risk. Niacin, aspirin, ACE inhibitors, angiotensin receptor blockers, beta blockers, ritonavir and pyrazinamide also increase it. The immunosuppressive drugs ciclosporin and tacrolimus are linked to gout too, and ciclosporin more so when combined with hydrochlorothiazide. Calcium channel blockers and losartan carry a lower risk than other blood pressure drugs.

  Sleep apnea can even be a hidden source, because oxygen-starved cells release purines. Treating the apnea can lessen the number of attacks.

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• 5. Finding the Crystals

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  A doctor can diagnose and treat gout without further tests when a patient has hyperuricemia and the classic acute arthritis at the base of the great toe. Synovial fluid analysis is recommended when the diagnosis is in doubt. Plain X-rays are usually normal in early gout, though they may reveal bone erosion in chronic cases.

  A definitive diagnosis rests on finding monosodium urate crystals in synovial fluid or in a tophus. Under polarized light microscopy they show a needle-like shape and strong negative birefringence. All fluid drawn by arthrocentesis from an undiagnosed inflamed joint should be checked for them. The test is difficult and needs a trained observer. The fluid must also be examined soon after aspiration, because temperature and pH affect how soluble the crystals are.

  The blood test for uric acid turns out to be weak evidence. Nearly half the time gout occurs without hyperuricemia, and most people with raised uric acid never develop gout. Hyperuricemia means a plasma urate level above 420 micromoles per litre, or 7.0 milligrams per decilitre, in males, and above 360 micromoles per litre, or 6.0 milligrams per decilitre, in females. Doctors also commonly check white blood cell count, electrolytes, kidney function and erythrocyte sedimentation rate. Both the white cell count and that rate can rise from gout alone, with no infection, and a white cell count as high as 40,000 per cubic millimetre has been documented.

  Septic arthritis, a joint infection, is the most important alternative diagnosis. It should be considered when a patient shows signs of infection or fails to improve with treatment, and a Gram stain and culture of the synovial fluid can help. Other lookalikes include CPPD, also called pseudogout, rheumatoid arthritis, psoriatic arthritis, palindromic rheumatism and reactive arthritis. Tophi that sit outside a joint can be mistaken for basal cell carcinoma or other neoplasms.

  A wrong guess carries real consequences, because glucocorticoids, a common gout treatment, make a joint infection worse.

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• 6. Treatment Options

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  Treatment has two aims. The first is to settle the symptoms of an acute attack, and the second is to prevent repeats with medicine that reduces serum uric acid. Lowering uric acid levels can cure the disease. Tentative evidence supports applying ice for 20 to 30 minutes several times a day to ease pain.

  Nonsteroidal anti-inflammatory drugs, or NSAIDs, are the usual first choice, and no single one is significantly better than another. Improvement may show within four hours, and treatment is recommended for one to two weeks. They are not advised for people with gastrointestinal bleeding, kidney failure or heart failure. Indometacin has historically been the most common choice, but ibuprofen may be preferred for its better side effect profile. A proton pump inhibitor can protect the stomach. COX-2 inhibitors may work as well with fewer side effects.

  Colchicine suits people who cannot tolerate NSAIDs. At high doses, mostly gastrointestinal upset limits its use, but lower doses still work and are well tolerated. It can interact with other common drugs, including atorvastatin and erythromycin.

  Glucocorticoids have been found as effective as NSAIDs and may be safer, and they also help when injected into the joint. No short-term adverse effects were reported.

  Canakinumab, an interleukin-1 inhibitor, showed moderate success in relieving pain and reducing joint swelling. It also raised the risk of back pain, headache and increased blood pressure, and it may work less well than usual doses of NSAIDs. Its high cost discourages use.

  As of 2020, allopurinol is generally the recommended drug for prevention. Long-term medicine is not advised until a person has had two attacks, unless destructive joint changes, tophi or urate nephropathy are present. It is not usually started until one to two weeks after a flare, and it is often paired with an NSAID or colchicine for the first three to six months. Allopurinol blocks uric acid production, is safe and well tolerated over the long term, and can be used in people with renal impairment or urate stones. A small number of people develop hypersensitivity. The HLA-B*58:01 allele is strongly associated with severe skin reactions to the drug, and it is most common among people of Korean, Han-Chinese or Thai descent.

  Febuxostat is recommended only for those who cannot tolerate allopurinol. There are concerns about more deaths with it, and it may increase flares early in treatment, although tentative evidence suggests it may lower urate more. Probenecid is a second-line option that appears less effective than allopurinol. It suits people who underexcrete uric acid, defined as less than 800 milligrams in a 24-hour urine sample, but not those with a history of kidney stones. Combined with allopurinol, it works better than allopurinol alone.

  Pegloticase is a third-line option for the 3% of people who are intolerant to other medicines. It is given by intravenous infusion every two weeks and helps shrink tophi, but it has a high rate of side effects and many people develop resistance. Lesinurad reduces blood uric acid by preventing absorption in the kidneys. It was approved in the United States for use with allopurinol in people who could not reach their uric acid targets, and its side effects include kidney problems and kidney stones.

  Anakinra, canakinumab and rilonacept are all under study. Canakinumab may give better outcomes than a low dose of a glucocorticoid, but it costs five thousand times more. A recombinant uricase enzyme called rasburicase is available, yet it triggers an immune response, so versions that are less antigenic are in development.

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• 7. Old Name, Old Disease

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  Around 1200 AD, an author named Randolphus of Bocking used the English word gout for the first time in surviving writing. It comes from the Latin gutta, meaning a drop of liquid. According to the Oxford English Dictionary, the word reflects humorism and the idea of a morbid material dropping from the blood into and around the joints.

  The disease itself is far older. The Ebers papyrus and the Edwin Smith papyrus, from about 1550 BC, each mention an arthritis they treat as a distinct type. They cite older Egyptian texts, now missing, that are claimed to have been written 1,000 years earlier and credited to Imhotep. Around 400 BC the Greek physician Hippocrates commented on gout in his Aphorisms, noting that it was absent in eunuchs and premenopausal women.

  Aulus Cornelius Celsus, writing in 30 AD, linked gout to alcohol, to later onset in women and to kidney problems. He observed that some people had obtained, in his words, "lifelong security by refraining from wine, mead and venery."

  Wits long called gout "the king of diseases and the disease of kings," and also "rich man's disease." Both names reflect its link with a rich diet and obesity.

  The first medical book devoted to the subject came from the English physician Benjamin Welles in 1669. He titled it A Treatise of the Gout, or Joint Evil.

  In 1679 the Dutch scientist Antonie van Leeuwenhoek became the first to describe how urate crystals look under the microscope. In the 18th century, Thomas Marryat sorted gout by location, calling it gonagra in the knees, chiragra in the hands, onagra in the elbow and omagra in the shoulder.

  The decisive step came in 1848, when the English physician Alfred Baring Garrod identified excess uric acid in the blood as the cause of gout. That finding set the stage for today's counting of who is affected.

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• 8. Who Gets Gout Today

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  Gout affects around 1-2% of people in the Western world at some point in their lives, and some 5.8 million people were affected in 2013. Rates approximately doubled between 1990 and 2010. The rise is believed to come from longer life expectancy, changes in diet and more of the diseases that travel with gout, such as metabolic syndrome and high blood pressure. Among men over 30 and women over 50, the rate is 2%. Older males are the group most commonly affected.

  In the United States, gout is twice as likely in males of African descent as in males of European descent. Rates are high among Polynesians, yet the disease is rare in aboriginal Australians, even though their mean uric acid concentration in the blood is higher. Gout has become common in China, Polynesia and urban Sub-Saharan Africa. Some studies found attacks more frequent in the spring, which has been attributed to seasonal shifts in diet, alcohol use, physical activity and temperature.

  Taiwan, Hong Kong and Singapore have a relatively high prevalence. A study using the National Health Insurance Research Database estimated that 4.92% of Taiwanese residents had gout in 2004. A Hong Kong government survey found gout in 5.1% of residents aged 45 to 59 and 6.1% of those older than 60. A 2015 study in Singapore found it in 2,117 of 52,322 people aged 45 to 74, roughly 4.1%.

  Fish, amphibians and most mammals other than primates all carry uricase, the enzyme that breaks down uric acid. That is why gout is rare in most other animals. Humans and the other great apes lost the ability to make it, and the loss helps explain why the condition is common in people. Avian gout is known to affect some bird species. One Tyrannosaurus rex specimen, known as Sue, is believed to have had gout.

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